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Journal articles on the topic 'Enhancers RNAs'
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1
Hah, Nasun, Chris Benner, Ling-Wa Chong, Ruth T. Yu, Michael Downes, and Ronald M. Evans. "Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs." Proceedings of the National Academy of Sciences 112, no. 3 (January 6, 2015): E297—E302. http://dx.doi.org/10.1073/pnas.1424028112.
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Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global nuclear run-on sequencing are extensively transcribed within super enhancers and are dynamically regulated in response to cellular signaling. Using Toll-like receptor 4 (TLR4) signaling in macrophages as a model system, we find that transcription of super enhancer-associated eRNAs is dynamically induced at most of the key genes driving innate immunity and inflammation. Unexpectedly, genes repressed by TLR4 signaling are also associated with super enhancer domains and accompanied by massive repression of eRNA transcription. Furthermore, we find each super enhancer acts as a single regulatory unit within which eRNA and genic transcripts are coordinately regulated. The key regulatory activity of these domains is further supported by the finding that super enhancer-associated transcription factor binding is twice as likely to be conserved between human and mouse than typical enhancer sites. Our study suggests that transcriptional activities at super enhancers are critical components to understand the dynamic gene regulatory network.
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de Lara, Josué Cortés-Fernández, Rodrigo G. Arzate-Mejía, and Félix Recillas-Targa. "Enhancer RNAs: Insights Into Their Biological Role." Epigenetics Insights 12 (January 2019): 251686571984609. http://dx.doi.org/10.1177/2516865719846093.
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Enhancers play a central role in the transcriptional regulation of metazoans. Almost a decade ago, the discovery of their pervasive transcription into noncoding RNAs, termed enhancer RNAs (eRNAs), opened a whole new field of study. The presence of eRNAs correlates with enhancer activity; however, whether they act as functional molecules remains controversial. Here we review direct experimental evidence supporting a functional role of eRNAs in transcription and provide a general pipeline that could help in the design of experimental approaches to investigate the function of eRNAs. We propose that induction of transcriptional activity at enhancers promotes an increase in its activity by an RNA-mediated titration of regulatory proteins that can impact different processes like chromatin accessibility or chromatin looping. In a few cases, transcripts originating from enhancers have acquired specific molecular functions to regulate gene expression. We speculate that these transcripts are either nonannotated long noncoding RNAs (lncRNAs) or are evolving toward functional lncRNAs. Further work will be needed to comprehend better the biological activity of these transcripts.
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Lewis, Michael W., Shen Li, and Hector L. Franco. "Transcriptional control by enhancers and enhancer RNAs." Transcription 10, no. 4-5 (October 20, 2019): 171–86. http://dx.doi.org/10.1080/21541264.2019.1695492.
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Kim, Tae-Kyung, Martin Hemberg, and Jesse M. Gray. "Enhancer RNAs: A Class of Long Noncoding RNAs Synthesized at Enhancers: Figure 1." Cold Spring Harbor Perspectives in Biology 7, no. 1 (January 2015): a018622. http://dx.doi.org/10.1101/cshperspect.a018622.
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Higgs, Douglas. "Regulated RNA Expression and Normal Erythropoiesis." Blood 124, no. 21 (December 6, 2014): SCI—34—SCI—34. http://dx.doi.org/10.1182/blood.v124.21.sci-34.sci-34.
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Although a small number of the vast array of long non-coding RNAs (lncRNAs) have known effects on cellular processes, in general their contribution to development, differentiation and disease remains unknown. We have shown that some intragenic enhancers, when active, behave as alternative promoters producing lncRNA transcripts that are processed using the canonical signals of their host gene. More recently we have also analyzed intergenic lncRNAs to determine the extent to which they too might originate from intergenic enhancers. We find that intergenic lncRNAs in erythroid cells are almost evenly divided between those arising from enhancer-associated or promoter-associated elements and that these RNAs differ with respect to their conservation and tissue specificity. Of considerable interest we find that expression of lncRNAs arising from enhancers is associated with enhanced expression of neighboring protein coding genes during erythropoiesis. Disclosures No relevant conflicts of interest to declare.
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Ibragimov, Airat N., Oleg V. Bylino, and Yulii V. Shidlovskii. "Molecular Basis of the Function of Transcriptional Enhancers." Cells 9, no. 7 (July 5, 2020): 1620. http://dx.doi.org/10.3390/cells9071620.
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Transcriptional enhancers are major genomic elements that control gene activity in eukaryotes. Recent studies provided deeper insight into the temporal and spatial organization of transcription in the nucleus, the role of non-coding RNAs in the process, and the epigenetic control of gene expression. Thus, multiple molecular details of enhancer functioning were revealed. Here, we describe the recent data and models of molecular organization of enhancer-driven transcription.
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Ørom, Ulf Andersson, and Ramin Shiekhattar. "Long non-coding RNAs and enhancers." Current Opinion in Genetics & Development 21, no. 2 (April 2011): 194–98. http://dx.doi.org/10.1016/j.gde.2011.01.020.
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Xu, Liang, Ye Chen, Yulun Huang, Edwin Sandanaraj, John S. Yu, Ruby Yu-Tong Lin, Pushkar Dakle, et al. "Topography of transcriptionally active chromatin in glioblastoma." Science Advances 7, no. 18 (April 2021): eabd4676. http://dx.doi.org/10.1126/sciadv.abd4676.
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Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer–driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM.
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Esse, Ruben, and Alla Grishok. "Caenorhabditis elegans Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions." Cells 9, no. 8 (August 6, 2020): 1846. http://dx.doi.org/10.3390/cells9081846.
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The methylation of histone H3 at lysine 79 is a feature of open chromatin. It is deposited by the conserved histone methyltransferase DOT1. Recently, DOT1 localization and H3K79 methylation (H3K79me) have been correlated with enhancers in C. elegans and mammalian cells. Since earlier research implicated H3K79me in preventing heterochromatin formation both in yeast and leukemic cells, we sought to inquire whether a H3K79me deficiency would lead to higher levels of heterochromatic histone modifications, specifically H3K9me2, at developmental enhancers in C. elegans. Therefore, we used H3K9me2 ChIP-seq to compare its abundance in control and dot-1.1 loss-of-function mutant worms, as well as in rde-4; dot-1.1 and rde-1; dot-1.1 double mutants. The rde-1 and rde-4 genes are components of the RNAi pathway in C. elegans, and RNAi is known to initiate H3K9 methylation in many organisms, including C. elegans. We have previously shown that dot-1.1(−) lethality is rescued by rde-1 and rde-4 loss-of-function. Here we found that H3K9me2 was elevated in enhancer, but not promoter, regions bound by the DOT-1.1/ZFP-1 complex in dot-1.1(−) worms. We also found increased H3K9me2 at genes targeted by the ALG-3/4-dependent small RNAs and repeat regions. Our results suggest that ectopic H3K9me2 in dot-1.1(−) could, in some cases, be induced by small RNAs.
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Carullo, Nancy V. N., Robert A. Phillips III, Rhiana C. Simon, Salomon A. Roman Soto, Jenna E. Hinds, Aaron J. Salisbury, Jasmin S. Revanna, et al. "Enhancer RNAs predict enhancer–gene regulatory links and are critical for enhancer function in neuronal systems." Nucleic Acids Research 48, no. 17 (August 18, 2020): 9550–70. http://dx.doi.org/10.1093/nar/gkaa671.
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Abstract Genomic enhancer elements regulate gene expression programs important for neuronal fate and function and are implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs). However, eRNA function remains controversial. Here, we combined Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq) and RNA-Seq datasets from three distinct neuronal culture systems in two activity states, enabling genome-wide enhancer identification and prediction of putative enhancer–gene pairs based on correlation of transcriptional output. Notably, stimulus-dependent enhancer transcription preceded mRNA induction, and CRISPR-based activation of eRNA synthesis increased mRNA at paired genes, functionally validating enhancer–gene predictions. Focusing on enhancers surrounding the Fos gene, we report that targeted eRNA manipulation bidirectionally modulates Fos mRNA, and that Fos eRNAs directly interact with the histone acetyltransferase domain of the enhancer-linked transcriptional co-activator CREB-binding protein (CBP). Together, these results highlight the unique role of eRNAs in neuronal gene regulation and demonstrate that eRNAs can be used to identify putative target genes.
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Wang, Rui, and Qianzi Tang. "Current Advances on the Important Roles of Enhancer RNAs in Molecular Pathways of Cancer." International Journal of Molecular Sciences 22, no. 11 (May 26, 2021): 5640. http://dx.doi.org/10.3390/ijms22115640.
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Enhancers are critical genomic elements that can cooperate with promoters to regulate gene transcription in both normal and cancer cells. Recent studies reveal that enhancer regions are transcribed to produce a class of noncoding RNAs referred to as enhancer RNAs (eRNAs). Emerging evidence shows that eRNAs play important roles in enhancer activation and enhancer-driven gene regulation, and the expression of eRNAs may be a critical factor in tumorigenesis. The important roles of eRNAs in cancer signaling pathways are also gradually unveiled, providing a new insight into cancer therapy. Here, we review the roles of eRNAs in regulating cancer signaling pathways and discuss the potential of eRNA-targeted therapy for human cancers.
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Ye, Rong, Changchang Cao, and Yuanchao Xue. "Enhancer RNA: biogenesis, function, and regulation." Essays in Biochemistry 64, no. 6 (December 2020): 883–94. http://dx.doi.org/10.1042/ebc20200014.
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Abstract Enhancers are noncoding DNA elements that are present upstream or downstream of a gene to control its spatial and temporal expression. Specific histone modifications, such as monomethylation on histone H3 lysine 4 (H3K4me1) and H3K27ac, have been widely used to assign enhancer regions in mammalian genomes. In recent years, emerging evidence suggests that active enhancers are bidirectionally transcribed to produce enhancer RNAs (eRNAs). This finding not only adds a new reliable feature to define enhancers but also raises a fundamental question of how eRNAs function to activate transcription. Although some believe that eRNAs are merely transcriptional byproducts, many studies have demonstrated that eRNAs execute crucial tasks in regulating chromatin conformation and transcription activation. In this review, we summarize the current understanding of eRNAs from their biogenesis, functions, and regulation to their pathological significance. Additionally, we discuss the challenges and possible mechanisms of eRNAs in regulated transcription.
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Liu, Yuhan, Mengting Ding, Qunjun Gao, Anbang He, Yuchen Liu, and Hongbing Mei. "Current Advances on the Important Roles of Enhancer RNAs in Gene Regulation and Cancer." BioMed Research International 2018 (2018): 1–6. http://dx.doi.org/10.1155/2018/2405351.
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Revealing the gene regulation networks governing cancer initiation and development is necessary while it remains uncompleted. In recent years, enhancers have been reported to be widely transcribed, resulting in the generation of enhancer RNAs (eRNAs). Previous studies have reported that eRNAs are a subclass of long noncoding RNAs (lncRNAs), which play a critical role in gene regulation and cancer development. These eRNAs can promote enhancer-promoter (E-P) looping formation by binding to other protein factors or propel expression of downstream protein-coding gene. In this review, we have focused on the characteristics of eRNAs and illustrated the biological function and potential mechanism of eRNAs in regulating gene expression and cancer development.
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Gushchanskaia, Ekaterina S., Ruben Esse, Qicheng Ma, Nelson C. Lau, and Alla Grishok. "Interplay between small RNA pathways shapes chromatin landscapes in C. elegans." Nucleic Acids Research 47, no. 11 (April 24, 2019): 5603–16. http://dx.doi.org/10.1093/nar/gkz275.
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Abstract The nematode Caenorhabditis elegans contains several types of endogenous small interfering RNAs (endo-siRNAs) produced by RNA-dependent RNA polymerase (RdRP) complexes. Both ‘silencing’ siRNAs bound by Worm-specific Argonautes (WAGO) and ‘activating’ siRNAs bound by the CSR-1 Argonaute require the DRH-3 helicase, an RdRP component. Here, we show that, in the drh-3(ne4253) mutant deficient in RdRP-produced secondary endo-siRNAs, the silencing histone mark H3K9me3 is largely depleted, whereas in the csr-1 partially rescued null mutant strain (WM193), this mark is ectopically deposited on CSR-1 target genes. Moreover, we observe ectopic H3K9me3 at enhancer elements and an increased number of small RNAs that match enhancers in both drh-3 and csr-1 mutants. Finally, we detect accumulation of H3K27me3 at highly expressed genes in the drh-3(ne4253) mutant, which correlates with their reduced transcription. Our study shows that when abundant RdRP-produced siRNAs are depleted, there is ectopic elevation of noncoding RNAs linked to sites with increased silencing chromatin marks. Moreover, our results suggest that enhancer small RNAs may guide local H3K9 methylation.
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Park, Angela, Soohwan Oh, Kyle L. Jung, Un Yung Choi, Hye-Ra Lee, Michael G. Rosenfeld, and Jae U. Jung. "Global epigenomic analysis of KSHV-infected primary effusion lymphoma identifies functionalMYCsuperenhancers and enhancer RNAs." Proceedings of the National Academy of Sciences 117, no. 35 (August 18, 2020): 21618–27. http://dx.doi.org/10.1073/pnas.1922216117.
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Enhancers play indispensable roles in cell proliferation and survival through spatiotemporally regulating gene transcription. Active enhancers and superenhancers often produce noncoding enhancer RNAs (eRNAs) that precisely control RNA polymerase II activity. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncogenic gamma-2 herpesvirus that causes Kaposi’s sarcoma and primary effusion lymphoma (PEL). It is well characterized that KSHV utilizes host epigenetic machineries to control the switch between two lifecycles, latency and lytic replication. However, how KSHV impacts host epigenome at different stages of viral lifecycle is not well understood. Using global run-on sequencing (GRO-seq) and chromatin-immunoprecipitation sequencing (ChIP-seq), we profiled the dynamics of host transcriptional regulatory elements during latency and lytic replication of KSHV-infected PEL cells. This revealed that a number of critical host genes for KSHV latency, includingMYCproto-oncogene, were under the control of superenhancers whose activities were globally repressed upon viral reactivation. The eRNA-expressingMYCsuperenhancers were located downstream of theMYCgene in KSHV-infected PELs and played a key role inMYCexpression. RNAi-mediated depletion or dCas9-KRAB CRISPR inhibition ofeRNAexpression significantly reducedMYCmRNA level in PELs, as did the treatment of an epigenomic drug that globally blocks superenhancer function. Finally, while cellular IRF4 acted uponeRNAexpression and superenhancer function forMYCexpression during latency, KSHV viral IRF4 repressed cellularIRF4expression, decreasingMYCexpression and thereby, facilitating lytic replication. These results indicate that KSHV acts as an epigenomic driver that modifies host epigenomic status upon reactivation by effectively regulating host enhancer function.
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Stone, Joshua K., Lana Vukadin, and Eun-Young Erin Ahn. "eNEMAL, an enhancer RNA transcribed from a distal MALAT1 enhancer, promotes NEAT1 long isoform expression." PLOS ONE 16, no. 5 (May 21, 2021): e0251515. http://dx.doi.org/10.1371/journal.pone.0251515.
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Emerging evidence has shown that active enhancers are abundantly transcribed, generating long non-coding RNAs, called enhancer RNAs (eRNAs). While putative eRNAs are often observed from RNA sequencing, the roles of most eRNAs remain largely unknown. Previously, we identified putative enhancer regions at the MALAT1 locus that form chromatin-chromatin interactions under hypoxia, and one of these enhancers is located about 30 kb downstream of the NEAT1 gene and -20 kb upstream of the MALAT1 gene (MALAT1–20 kb enhancer). Here, we report that a novel eRNA, named eRNA of the NEAT1-MALAT1-Locus (eNEMAL), is transcribed from the MALAT1–20 kb enhancer and conserved in primates. We found that eNEMAL is upregulated in response to hypoxia in multiple breast cancer cell lines, but not in non-tumorigenic MCF10A cells. Overexpression and knockdown of eNEMAL revealed that alteration of eNEMAL level does not affect MALAT1 expression. Instead, we found that eNEMAL upregulates the long isoform of NEAT1 (NEAT1_2) without increasing the total NEAT1 transcript level in MCF7 breast cancer cells, suggesting that eNEMAL has a repressive effect on the 3’-end polyadenylation process required for generating the short isoform of NEAT1 (NEAT1_1). Altogether, we demonstrated that an eRNA transcribed from a MALAT1 enhancer regulates NEAT1 isoform expression, implicating the MALAT1–20 kb enhancer and its transcript eNEMAL in co-regulation of MALAT1 and NEAT1 in response to hypoxia in breast cancer cells.
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Coulter, L. R., M. A. Landree, and T. A. Cooper. "Identification of a new class of exonic splicing enhancers by in vivo selection." Molecular and Cellular Biology 17, no. 4 (April 1997): 2143–50. http://dx.doi.org/10.1128/mcb.17.4.2143.
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In vitro selection strategies have typically been used to identify a preferred ligand, usually an RNA, for an identified protein. Ideally, one would like to know RNA consensus sequences preferred in vivo for as-yet-unidentified factors. The ability to select RNA-processing signals would be particularly beneficial in the analysis of exon enhancer sequences that function in exon recognition during pre-mRNA splicing. Exon enhancers represent a class of potentially ubiquitous RNA-processing signals whose actual prevalence is unknown. To establish an approach for in vivo selection, we developed an iterative scheme to select for exon sequences that enhance exon inclusion. This approach is modeled on the in vitro SELEX procedure and uses transient transfection in an iterative procedure to enrich RNA-processing signals in cultured vertebrate cells. Two predominant sequence motifs were enriched after three rounds of selection: a purine-rich motif that resembles previously identified splicing enhancers and a class of A/C-rich splicing enhancers (ACEs). Individual selected ACEs enhanced splicing in vivo and in vitro. ACE splicing activity was competed by RNAs containing the purine-rich splicing enhancer from cardiac troponin T exon 5. Thus, ACE activity is likely to require a subset of the SR splicing factors previously shown to mediate activity of this purine-rich enhancer. ACE motifs are found in two vertebrate exons previously demonstrated to contain splicing enhancer activity as well as in the well-characterized Drosophila doublesex (dsx) splicing enhancer. We demonstrate that one copy of the dsx repeat enhances splicing of a vertebrate exon in vertebrate cells and that this enhancer activity requires the ACE motif. We suggest the possibility that the dsx enhancer is a member of a previously unrecognized family of ACEs.
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Orom, U. A., T. Derrien, R. Guigo, and R. Shiekhattar. "Long Noncoding RNAs as Enhancers of Gene Expression." Cold Spring Harbor Symposia on Quantitative Biology 75 (January 1, 2010): 325–31. http://dx.doi.org/10.1101/sqb.2010.75.058.
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Tan, Jennifer Y., Adriano Biasini, Robert S. Young, and Ana C. Marques. "Splicing of enhancer-associated lincRNAs contributes to enhancer activity." Life Science Alliance 3, no. 4 (February 21, 2020): e202000663. http://dx.doi.org/10.26508/lsa.202000663.
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Transcription is common at active mammalian enhancers sometimes giving rise to stable enhancer-associated long intergenic noncoding RNAs (elincRNAs). Expression of elincRNA is associated with changes in neighboring gene product abundance and local chromosomal topology, suggesting that transcription at these loci contributes to gene expression regulation in cis. Despite the lack of evidence supporting sequence-dependent functions for most elincRNAs, splicing of these transcripts is unexpectedly common. Whether elincRNA splicing is a mere consequence of cognate enhancer activity or if it directly impacts enhancer function remains unresolved. Here, we investigate the association between elincRNA splicing and enhancer activity in mouse embryonic stem cells. We show that multi-exonic elincRNAs are enriched at conserved enhancers, and the efficient processing of elincRNAs is strongly associated with their cognate enhancer activity. This association is supported by their enrichment in enhancer-specific chromatin signatures; elevated binding of co-transcriptional regulators; increased local intra-chromosomal DNA contacts; and strengthened cis-regulation on target gene expression. Our results support the role of efficient RNA processing of enhancer-associated transcripts to cognate enhancer activity.
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Brazão, Tiago F., Jethro S. Johnson, Jennifer Müller, Andreas Heger, Chris P. Ponting, and Victor L. J. Tybulewicz. "Long noncoding RNAs in B-cell development and activation." Blood 128, no. 7 (August 18, 2016): e10-e19. http://dx.doi.org/10.1182/blood-2015-11-680843.
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AbstractLong noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.
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Matsuyama, Hironori, and Hiroshi I. Suzuki. "Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis." International Journal of Molecular Sciences 21, no. 1 (December 24, 2019): 132. http://dx.doi.org/10.3390/ijms21010132.
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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA–target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.
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Ørom, Ulf Andersson, and Ramin Shiekhattar. "Noncoding RNAs and enhancers: complications of a long-distance relationship." Trends in Genetics 27, no. 10 (October 2011): 433–39. http://dx.doi.org/10.1016/j.tig.2011.06.009.
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Ishov, Alexander M., Aishwarya Gurumurthy, and Jörg Bungert. "Coordination of transcription, processing, and export of highly expressed RNAs by distinct biomolecular condensates." Emerging Topics in Life Sciences 4, no. 3 (April 27, 2020): 281–91. http://dx.doi.org/10.1042/etls20190160.
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Genes under control of super-enhancers are expressed at extremely high levels and are frequently associated with nuclear speckles. Recent data suggest that the high concentration of unphosphorylated RNA polymerase II (Pol II) and Mediator recruited to super-enhancers create phase-separated condensates. Transcription initiates within or at the surface of these phase-separated droplets and the phosphorylation of Pol II, associated with transcription initiation and elongation, dissociates Pol II from these domains leading to engagement with nuclear speckles, which are enriched with RNA processing factors. The transitioning of Pol II from transcription initiation domains to RNA processing domains effectively co-ordinates transcription and processing of highly expressed RNAs which are then rapidly exported into the cytoplasm.
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Pnueli, Lilach, Sergei Rudnizky, Yahav Yosefzon, and Philippa Melamed. "RNA transcribed from a distal enhancer is required for activating the chromatin at the promoter of the gonadotropin α-subunit gene." Proceedings of the National Academy of Sciences 112, no. 14 (March 25, 2015): 4369–74. http://dx.doi.org/10.1073/pnas.1414841112.
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Since the discovery that many transcriptional enhancers are transcribed into long noncoding RNAs termed “enhancer RNAs” (eRNAs), their putative role in enhancer function has been debated. Very recent evidence has indicted that some eRNAs play a role in initiating or activating transcription, possibly by helping recruit and/or stabilize binding of the general transcription machinery to the proximal promoter of their target genes. The distal enhancer of the gonadotropin hormone α-subunit gene, chorionic gonadotropin alpha (Cga), is responsible for Cga cell-specific expression in gonadotropes and thyrotropes, and we show here that it encodes two bidirectional nonpolyadenylated RNAs whose levels are increased somewhat by exposure to gonadotropin-releasing hormone but are not necessarily linked to Cga transcriptional activity. Knockdown of the more distal eRNA led to a drop in Cga mRNA levels, initially without effect on the forward eRNA levels. With time, however, the repression on the Cga increased, and the forward eRNA levels were suppressed also. We demonstrate that the interaction of the enhancer with the promoter is lost after eRNA knockdown. Dramatic changes also were seen in the chromatin, with an increase in total histone H3 occupancy throughout this region and a virtual loss of histone H3 Lys 4 trimethylation at the promoter following the eRNA knockdown. Moreover, histone H3 Lys 27 (H3K27) acetylation, which was found at both enhancer and promoter in wild-type cells, appeared to have been replaced by H3K27 trimethylation at the enhancer. Thus, the Cga eRNA mediates the physical interaction between these genomic regions and determines the chromatin structure of the proximal promoter to allow gene expression.
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Papanicolaou, Natali, and Alessandro Bonetti. "The New Frontier of Functional Genomics: From Chromatin Architecture and Noncoding RNAs to Therapeutic Targets." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 6 (June 2, 2020): 568–80. http://dx.doi.org/10.1177/2472555220926158.
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Common diseases are complex, multifactorial disorders whose pathogenesis is influenced by the interplay of genetic predisposition and environmental factors. Genome-wide association studies have interrogated genetic polymorphisms across genomes of individuals to test associations between genotype and susceptibility to specific disorders, providing insights into the genetic architecture of several complex disorders. However, genetic variants associated with the susceptibility to common diseases are often located in noncoding regions of the genome, such as tissue-specific enhancers or long noncoding RNAs, suggesting that regulatory elements might play a relevant role in human diseases. Enhancers are cis-regulatory genomic sequences that act in concert with promoters to regulate gene expression in a precise spatiotemporal manner. They can be located at a considerable distance from their cognate target promoters, increasing the difficulty of their identification. Genomes are organized in domains of chromatin folding, namely topologically associating domains (TADs). Identification of enhancer–promoter interactions within TADs has revealed principles of cell-type specificity across several organisms and tissues. The vast majority of mammalian genomes are pervasively transcribed, accounting for a previously unappreciated complexity of the noncoding RNA fraction. Particularly, long noncoding RNAs have emerged as key players for the establishment of chromatin architecture and regulation of gene expression. In this perspective, we describe the new advances in the fields of transcriptomics and genome organization, focusing on the role of noncoding genomic variants in the predisposition of common diseases. Finally, we propose a new framework for the identification of the next generation of pharmacological targets for common human diseases.
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Staknis, D., and R. Reed. "SR proteins promote the first specific recognition of Pre-mRNA and are present together with the U1 small nuclear ribonucleoprotein particle in a general splicing enhancer complex." Molecular and Cellular Biology 14, no. 11 (November 1994): 7670–82. http://dx.doi.org/10.1128/mcb.14.11.7670.
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We show that addition of SR proteins to in vitro splicing extracts results in a significant increase in assembly of the earliest prespliceosomal complex E and a corresponding decrease in assembly of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex H. In addition, SR proteins promote formation of the E5' and E3' complexes that assemble on RNAs containing only 5' and 3' splice sites, respectively. We conclude that SR proteins promote the earliest specific recognition of both the 5' and 3' splice sites and are limiting for this function in HeLa nuclear extracts. Using UV cross-linking, we demonstrate specific, splice site-dependent RNA-protein interactions of SR proteins in the E, E5', and E3' complexes. SR proteins do not UV cross-link in the H complex, and conversely, hnRNP cross-linking is largely excluded from the E-type complexes. We also show that a discrete complex resembling the E5' complex assembles on both purine-rich and non-purine-rich exonic splicing enhancers. This complex, which we have designated the Enhancer complex, contains U1 small nuclear RNP (snRNP) and is associated with different SR protein family members, depending on the sequence of the enhancer. We propose that both downstream 5' splice site enhancers and exonic enhancers function by establishing a network of pre-mRNA-protein and protein-protein interactions involving U1 snRNP, SR proteins, and U2AF that is similar to the interactions that bring the 5' and 3' splice sites together in the E complex.
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Staknis, D., and R. Reed. "SR proteins promote the first specific recognition of Pre-mRNA and are present together with the U1 small nuclear ribonucleoprotein particle in a general splicing enhancer complex." Molecular and Cellular Biology 14, no. 11 (November 1994): 7670–82. http://dx.doi.org/10.1128/mcb.14.11.7670-7682.1994.
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We show that addition of SR proteins to in vitro splicing extracts results in a significant increase in assembly of the earliest prespliceosomal complex E and a corresponding decrease in assembly of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex H. In addition, SR proteins promote formation of the E5' and E3' complexes that assemble on RNAs containing only 5' and 3' splice sites, respectively. We conclude that SR proteins promote the earliest specific recognition of both the 5' and 3' splice sites and are limiting for this function in HeLa nuclear extracts. Using UV cross-linking, we demonstrate specific, splice site-dependent RNA-protein interactions of SR proteins in the E, E5', and E3' complexes. SR proteins do not UV cross-link in the H complex, and conversely, hnRNP cross-linking is largely excluded from the E-type complexes. We also show that a discrete complex resembling the E5' complex assembles on both purine-rich and non-purine-rich exonic splicing enhancers. This complex, which we have designated the Enhancer complex, contains U1 small nuclear RNP (snRNP) and is associated with different SR protein family members, depending on the sequence of the enhancer. We propose that both downstream 5' splice site enhancers and exonic enhancers function by establishing a network of pre-mRNA-protein and protein-protein interactions involving U1 snRNP, SR proteins, and U2AF that is similar to the interactions that bring the 5' and 3' splice sites together in the E complex.
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Yang, Mei, Ji Hoon Lee, Zhao Zhang, Richard De La Rosa, Mingjun Bi, Yuliang Tan, Yiji Liao, et al. "Enhancer RNAs Mediate Estrogen-Induced Decommissioning of Selective Enhancers by Recruiting ERα and Its Cofactor." Cell Reports 31, no. 12 (June 2020): 107803. http://dx.doi.org/10.1016/j.celrep.2020.107803.
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Zhang, Yuwei, Dechao Bu, Peipei Huo, Zhihao Wang, Hao Rong, Yanguo Li, Jingjia Liu, et al. "ncFANs v2.0: an integrative platform for functional annotation of non-coding RNAs." Nucleic Acids Research 49, W1 (May 29, 2021): W459—W468. http://dx.doi.org/10.1093/nar/gkab435.
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Abstract Increasing evidence proves the essential regulatory roles of non-coding RNAs (ncRNAs) in biological processes. However, characterizing the specific functions of ncRNAs remains a challenging task, owing to the intensive consumption of the experimental approaches. Here, we present an online platform ncFANs v2.0 that is a significantly enhanced version of our previous ncFANs to provide multiple computational methods for ncRNA functional annotation. Specifically, ncFANs v2.0 was updated to embed three functional modules, including ncFANs-NET, ncFANs-eLnc and ncFANs-CHIP. ncFANs-NET is a new module designed for data-free functional annotation based on four kinds of pre-built networks, including the co-expression network, co-methylation network, long non-coding RNA (lncRNA)-centric regulatory network and random forest-based network. ncFANs-eLnc enables the one-stop identification of enhancer-derived lncRNAs from the de novo assembled transcriptome based on the user-defined or our pre-annotated enhancers. Moreover, ncFANs-CHIP inherits the original functions for microarray data-based functional annotation and supports more chip types. We believe that our ncFANs v2.0 carries sufficient convenience and practicability for biological researchers and facilitates unraveling the regulatory mechanisms of ncRNAs. The ncFANs v2.0 server is freely available at http://bioinfo.org/ncfans or http://ncfans.gene.ac.
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Liang, Jun, Hufeng Zhou, Catherine Gerdt, Min Tan, Tyler Colson, Kenneth M. Kaye, Elliott Kieff, and Bo Zhao. "Epstein–Barr virus super-enhancer eRNAs are essential for MYC oncogene expression and lymphoblast proliferation." Proceedings of the National Academy of Sciences 113, no. 49 (November 18, 2016): 14121–26. http://dx.doi.org/10.1073/pnas.1616697113.
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Epstein–Barr virus (EBV) super-enhancers (ESEs) are essential for lymphoblastoid cell (LCL) growth and survival. Reanalyses of LCL global run-on sequencing (Gro-seq) data found abundant enhancer RNAs (eRNAs) being transcribed at ESEs. Inactivation of ESE components, EBV nuclear antigen 2 (EBNA2) and bromodomain-containing protein 4 (BRD4), significantly decreased eRNAs at ESEs −428 and −525 kb upstream of the MYC oncogene transcription start site (TSS). shRNA knockdown of the MYC −428 and −525 ESE eRNA caused LCL growth arrest and reduced cell growth. Furthermore, MYC ESE eRNA knockdown also significantly reduced MYC expression, ESE H3K27ac signals, and MYC ESEs looping to MYC TSS. These data indicate that ESE eRNAs strongly affect cell gene expression and enable LCL growth.
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Rothschild, Gerson, Wanwei Zhang, Junghyun Lim, Pankaj Kumar Giri, Brice Laffleur, Yiyun Chen, Mingyan Fang, et al. "Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination." Science Immunology 5, no. 44 (February 7, 2020): eaay5864. http://dx.doi.org/10.1126/sciimmunol.aay5864.
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B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell–specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3′ regulatory region (3′RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome–deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer’s patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3′RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer’s patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.
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Ørom, Ulf Andersson, and Ramin Shiekhattar. "Long Noncoding RNAs Usher In a New Era in the Biology of Enhancers." Cell 154, no. 6 (September 2013): 1190–93. http://dx.doi.org/10.1016/j.cell.2013.08.028.
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Wang, Bin, Jing Sun, Jiandong Shi, Qing Guo, Xiangrong Tong, Jin Zhang, Ningzhu Hu, and YunZhang Hu. "Small-Activating RNA Can Change Nucleosome Positioning in Human Fibroblasts." Journal of Biomolecular Screening 21, no. 6 (March 18, 2016): 634–42. http://dx.doi.org/10.1177/1087057116637562.
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RNA activation (RNAa) is a mechanism of positive gene expression regulation mediated by small-activating RNAs (saRNAs), which target gene promoters and have been used as tools to manipulate gene expression. Studies have shown that RNAa is associated with epigenetic modifications at promoter regions; however, it is unclear whether these modifications are the cause or a consequence of RNAa. In this study, we examined changes in nucleosome repositioning and the involvement of RNA polymerase II (RNAPII) in this process. We screened saRNAs for OCT4 ( POU5F1), SOX2, and NANOG, and identified several novel saRNAs. We found that nucleosome positioning was altered after saRNA treatment and that the formation of nucleosome-depleted regions (NDRs) contributed to RNAa at sites of RNAPII binding, such as the TATA box, CpG islands (CGIs), proximal enhancers, and proximal promoters. Moreover, RNAPII appeared to be bound specifically to NDRs. These results suggested that changes in nucleosome positions resulted from RNAa. We thus propose a hypothesis that targeting promoter regions using exogenous saRNAs can induce the formation of NDRs, exposing regulatory binding sites to recruit RNAPII, a key component of preinitiation complex, and leading to increased initiation of transcription.
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Gao, Yue, Xin Li, Shipeng Shang, Shuang Guo, Peng Wang, Dailin Sun, Jing Gan, et al. "LincSNP 3.0: an updated database for linking functional variants to human long non-coding RNAs, circular RNAs and their regulatory elements." Nucleic Acids Research 49, no. D1 (November 21, 2020): D1244—D1250. http://dx.doi.org/10.1093/nar/gkaa1037.
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Abstract We describe an updated comprehensive database, LincSNP 3.0 (http://bioinfo.hrbmu.edu.cn/LincSNP), which aims to document and annotate disease or phenotype-associated variants in human long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) or their regulatory elements. LincSNP 3.0 has updated with several novel features, including (i) more types of variants including single nucleotide polymorphisms (SNPs), linkage disequilibrium SNPs (LD SNPs), somatic mutations and RNA editing sites have been expanded; (ii) more regulatory elements including transcription factor binding sites (TFBSs), enhancers, DNase I hypersensitive sites (DHSs), topologically associated domains (TADs), footprintss, methylations and open chromatin regions have been added; (iii) the associations among circRNAs, regulatory elements and variants have been identified; (iv) more experimentally supported variant-lncRNA/circRNA-disease/phenotype associations have been manually collected; (v) the sources of lncRNAs, circRNAs, SNPs, somatic mutations and RNA editing sites have been updated. Moreover, four flexible online tools including Genome Browser, Variant Mapper, Circos Plotter and Functional Annotation have been developed to retrieve, visualize and analyze the data. Collectively, LincSNP 3.0 provides associations among functional variants, regulatory elements, lncRNAs and circRNAs in diseases. It will serve as an important and continually updated resource for investigating functions and mechanisms of lncRNAs and circRNAs in diseases.
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Benbarche, Salima, Cécile K. Lopez, Thomas Mercher, and Camille Lobry. "Crispri-Based Screening of Clustered Regulatory Elements Reveals Novel Leukemia Dependencies." Blood 132, Supplement 1 (November 29, 2018): 654. http://dx.doi.org/10.1182/blood-2018-99-111865.
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Abstract In the recent years, massively parallel sequencing approaches allowed the identification of hundreds of mutated genes in Leukemia. Although these data gave unprecedented amount of information about mechanisms of leukemia cell maintenance and/or progression, the functional characterization of genes that are key player in regulating cancer development remain laborious. Analysis at the single gene level often fails to identify gene or pathway collaborations leading to transformation. Studies aimed at depicting new oncogene cooperation would involve the generation of challenging mouse models or the deployment of tedious screening pipelines, which would be inadequate to depict new oncogene circuitry in cancer. Genome wide mapping of epigenetic modifications on histone tails or binding of factors such as MED1 and BRD4 allowed identification of clusters of regulatory elements, also termed as Super Enhancers. Functional annotation of these regions revealed their high relevance during normal hematopoiesis and Leukemogenesis. We hypothesized that these regulatory regions could regulate simultaneously expression of genes cooperating to promote Leukemia development. We thus developed a novel genome-wide CRISPRi-based screening approach to directly target these regulatory regions. CRISPRi technology relies on the use of deactivated Cas9 that can't cut the DNA and that is fused to the repressive KRAB domain (dCas9-KRAB). Therefore, properly targeted dCas9-KRAB by single guide RNAs will recruit chromatin modifying factors and trigger generation of heterochromatin thus inhibiting enhancer function. We performed this screen using acute megakaryoblastic leukemia model driven by the CBFA2T3-GLIS2 fusion, the most frequent fusion oncogene in this disease that we recently identified as being associated with Super Enhancers (Thirant et al, Cancer Cell 2017). To inhibit Super Enhancer activity we integrated ChIP-seq data of H3K27ac and ATAC-seq data to define open chromatin regions located in Super Enhancers. We designed a library of 7995 single guide RNAs targeting 450 Super Enhancer regions found active in CBFA2T3-GLIS2 bearing cell line M07e and primary AMKL patient samples. This screening methodology allowed us to nominate Super Enhancer regions, which are functionally linked to leukemia progression. In particular, we pinpointed a novel Super Enhancer region, induced by CBFA2T3-GLIS2 fusion, regulating the expression of both tyrosine kinases associated receptors KIT and PDGFRA. We were able to show that this Super Enhancer region is normally not active in normal megakaryocytic development and aberrantly induced by CBFA2T3-GLIS2 expression. RNA-sequencing experiments and 4C-seq experiments (chromatin conformation capture) showed that this Super Enhancer is directly regulating KIT and PDGFRA expression. Whereas single inhibition of these genes using shRNA or small molecule inhibitors affects modestly leukemic cell growth, concomitant inhibition of these two receptors synergizes to impair AMKL cell lines and primary patient cells growth and survival. In vivo targeting of this Super Enhancer activity in patient-derived xenograft models using CRISPRi showed significant reduction of tumor burden and increased overall survival. Our results demonstrate that genome-wide screening of regulatory DNA elements can identify co-regulated genes collaborating to promote leukemia progression and could open new avenues for the design of combination therapies. Reference: Thirant C, Ignacimouttou C, Lopez CK, Diop M, Le Mouël L, Thiollier C, Siret A, Dessen P, Aid Z, Rivière J, Rameau P, Lefebvre C, Khaled M, Leverger G, Ballerini P, Petit A, Raslova H, Carmichael CL, Kile BT, Soler E, Crispino JD, Wichmann C, Pflumio F, Schwaller J, Vainchenker W, Lobry C, Droin N, Bernard OA, Malinge S, Mercher T (2017). ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. Cancer Cell. 31(3):452-465. Disclosures No relevant conflicts of interest to declare.
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Bergstrom, D. E., C. A. Merli, J. A. Cygan, R. Shelby, and R. K. Blackman. "Regulatory autonomy and molecular characterization of the Drosophila out at first gene." Genetics 139, no. 3 (March 1, 1995): 1331–46. http://dx.doi.org/10.1093/genetics/139.3.1331.
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Abstract Our previous work has shown that the expression of the Drosophila decapentaplegic (dpp) gene in imaginal disks is controlled by a 30 kb array of enhancers located 3' of the dpp coding region. Here, we describe the cloning and characterization of out at first (oaf), a gene located near this enhancer region. Transcription of oaf results in three classes of alternatively polyadenylated RNAs whose expression is developmentally regulated. All oaf transcripts contain two adjacent open reading frames separated by a single UGA stop codon. Suppression of the UGA codon during translation, as seen previously in Drosophila, could lead to the production of different proteins from the same RNA. During oogenesis, oaf RNA is expressed in nurse cells of all ages and maternally contributed to the egg. During embryonic development, zygotic transcription of the gene occurs in small clusters of cells in most or all segments at the time of germband extension and subsequently in a segmentally repeated pattern in the developing central nervous system. The gene is also expressed in the embryonic, larval and adult gonads of both sexes. We also characterize an enhancer trap line with its transposon inserted within the oaf gene and use it to generate six recessive oaf mutations. All six cause death near the beginning of the first larval instar, with two characterized lines showing nervous system defects. Last, we discuss our data in light of the observation that the enhancers controlling dpp expression in the imaginal disks have no effect on the relatively nearby oaf gene.
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Karetnikov, Alexey, and Kirsi Lehto. "The RNA2 5′ leader of Blackcurrant reversion virus mediates efficient in vivo translation through an internal ribosomal entry site mechanism." Journal of General Virology 88, no. 1 (January 1, 2007): 286–97. http://dx.doi.org/10.1099/vir.0.82307-0.
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The 5′ and 3′ non-translated regions (NTRs) of mRNAs of eukaryotes and their viruses often contain translational enhancers, including internal ribosomal entry sites (IRESs) comprised in the 5′ leaders of many uncapped viral mRNAs. Blackcurrant reversion virus (BRV) has a genome composed of two uncapped, polyadenylated RNAs with relatively short 5′ NTRs, almost devoid of secondary structure. In this work, a role of the RNA2 5′ NTR in translation was studied by using mono- and dicistronic Photinus pyralis and Renilla reniformis luciferase reporter mRNAs in protoplasts of Nicotiana benthamiana. The RNA2 5′ leader was found to confer efficient in vivo translation compared with the control 5′ NTR, and each half of the BRV leader was essential for stimulatory function. Such efficient translational enhancement was mediated, at least in part, through an IRES mechanism. Multiple RNA2 5′ NTR regions, complementary to a fragment of plant 18S rRNA demonstrated previously to be accessible for intermolecular mRNA–rRNA interactions and conserved between eukaryotes, were shown to be important for efficient translation. Similar mRNA–rRNA base-pairing potential was also predicted for the 5′ leaders of other nepoviruses.
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Das, Sadhan, Marpadga A. Reddy, and Rama Natarajan. "Role of epigenetic mechanisms regulated by enhancers and long noncoding RNAs in cardiovascular disease." Current Opinion in Cardiology 35, no. 3 (May 2020): 234–41. http://dx.doi.org/10.1097/hco.0000000000000728.
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Cheng, Donghang, Vidyasiri Vemulapalli, Yue Lu, Jianjun Shen, Sayura Aoyagi, Christopher J. Fry, Yanzhong Yang, et al. "CARM1 methylates MED12 to regulate its RNA-binding ability." Life Science Alliance 1, no. 5 (September 19, 2018): e201800117. http://dx.doi.org/10.26508/lsa.201800117.
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The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator of transcription by methylating a diverse array of substrates. To broaden our understanding of CARM1's mechanistic actions, we sought to identify additional substrates for this enzyme. To do this, we generated CARM1 substrate motif antibodies, and used immunoprecipitation coupled with mass spectrometry to identify cellular targets of CARM1, including mediator complex subunit 12 (MED12) and the lysine methyltransferase KMT2D. Both of these proteins are implicated in enhancer function. We identified the major CARM1-mediated MED12 methylation site as arginine 1899 (R1899), which interacts with the Tudor domain–containing effector molecule, TDRD3. Chromatin immunoprecipitation–seq studies revealed that CARM1 and the methyl mark it deposits are tightly associated with ERα-specific enhancers and positively modulate transcription of estrogen-regulated genes. In addition, we showed that the methylation of MED12, at the R1899 site, and the recruitment of TDRD3 by this methylated motif are critical for the ability of MED12 to interact with activating noncoding RNAs.
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Wang, Ke, Lantian Wang, Jianshu Wang, Suli Chen, Min Shi, and Hong Cheng. "Intronless mRNAs transit through nuclear speckles to gain export competence." Journal of Cell Biology 217, no. 11 (September 7, 2018): 3912–29. http://dx.doi.org/10.1083/jcb.201801184.
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Nuclear speckles (NSs) serve as splicing factor storage sites. In this study, we unexpectedly found that many endogenous intronless mRNAs, which do not undergo splicing, associate with NSs. These associations do not require transcription, polyadenylation, or the polyA tail. Rather, exonic splicing enhancers present in intronless mRNAs and their binding partners, SR proteins, promote intronless mRNA localization to NSs. Significantly, speckle targeting of mRNAs promotes the recruitment of the TREX export complex and their TREX-dependent nuclear export. Furthermore, TREX, which accumulates in NSs, is required for releasing intronless mRNAs from NSs, whereas NXF1, which is mainly detected at nuclear pores, is not. Upon NXF1 depletion, the TREX protein UAP56 loses speckle concentration but coaccumulates with intronless mRNAs and polyA RNAs in the nucleoplasm, and these RNAs are trapped in NSs upon UAP56 codepletion. We propose that the export-competent messenger RNP assembly mainly occurs in NSs for intronless mRNAs and that entering NSs serves as a quality control step in mRNA export.
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Baumgart, Simon J., Ekaterina Nevedomskaya, and Bernard Haendler. "Dysregulated Transcriptional Control in Prostate Cancer." International Journal of Molecular Sciences 20, no. 12 (June 13, 2019): 2883. http://dx.doi.org/10.3390/ijms20122883.
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Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions of the genome and lead to dysregulated gene expression. Single nucleotide variations and small mutations affecting the recruitment of transcription factor complexes to DNA regulatory elements are observed in an increasing number of cases. Genomic rearrangements may position coding regions under the novel control of regulatory elements, as exemplified by the TMPRSS2-ERG fusion and the amplified enhancer identified upstream of the androgen receptor (AR) gene. Super-enhancers are increasingly found to play important roles in aberrant oncogenic transcription. Several players involved in these processes are currently being evaluated as drug targets and may represent new vulnerabilities that can be exploited for prostate cancer treatment. They include factors involved in enhancer and super-enhancer function such as bromodomain proteins and cyclin-dependent kinases. In addition, non-coding RNAs with an important gene regulatory role are being explored. The rapid progress made in understanding the influence of the non-coding part of the genome and of transcription dysregulation in prostate cancer could pave the way for the identification of novel treatment paradigms for the benefit of patients.
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Wong, Wilson K. M., Anja E. Sørensen, Mugdha V. Joglekar, Anand A. Hardikar, and Louise T. Dalgaard. "Non-Coding RNA in Pancreas and β-Cell Development." Non-Coding RNA 4, no. 4 (December 13, 2018): 41. http://dx.doi.org/10.3390/ncrna4040041.
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In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.
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Thomas, Amarni L., Judith Marsman, Jisha Antony, William Schierding, Justin M. O’Sullivan, and Julia A. Horsfield. "Transcriptional Regulation of RUNX1: An Informatics Analysis." Genes 12, no. 8 (July 29, 2021): 1175. http://dx.doi.org/10.3390/genes12081175.
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The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.
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Fan, Zenghua, Meng Zhao, Parth D. Joshi, Ping Li, Yan Zhang, Weimin Guo, Yichi Xu, Haifang Wang, Zhihu Zhao, and Jun Yan. "A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation." Nucleic Acids Research 45, no. 10 (March 8, 2017): 5720–38. http://dx.doi.org/10.1093/nar/gkx156.
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Carlo, Troy, Rebecca Sierra, and Susan M. Berget. "A 5′ Splice Site-Proximal Enhancer Binds SF1 and Activates Exon Bridging of a Microexon." Molecular and Cellular Biology 20, no. 11 (June 1, 2000): 3988–95. http://dx.doi.org/10.1128/mcb.20.11.3988-3995.2000.
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ABSTRACT Internal exon size in vertebrates occurs over a narrow size range. Experimentally, exons shorter than 50 nucleotides are poorly included in mRNA unless accompanied by strengthened splice sites or accessory sequences that act as splicing enhancers, suggesting steric interference between snRNPs and other splicing factors binding simultaneously to the 3′ and 5′ splice sites of microexons. Despite these problems, very small naturally occurring exons exist. Here we studied the factors and mechanism involved in recognizing a constitutively included six-nucleotide exon from the cardiac troponin T gene. Inclusion of this exon is dependent on an enhancer located downstream of the 5′ splice site. This enhancer contains six copies of the simple sequence GGGGCUG. The enhancer activates heterologous microexons and will work when located either upstream or downstream of the target exon, suggesting an ability to bind factors that bridge splicing units. A single copy of this sequence is sufficient for in vivo exon inclusion and is the binding site for the known bridging mammalian splicing factor 1 (SF1). The enhancer and its bound SF1 act to increase recognition of the upstream exon during exon definition, such that competition of in vitro reactions with RNAs containing the GGGGCUG repeated sequence depress splicing of the upstream intron, assembly of the spliceosome on the 3′ splice site of the exon, and cross-linking of SF1. These results suggest a model in which SF1 bridges the small exon during initial assembly, thereby effectively extending the domain of the exon.
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Pospisil, Vitek, Pavle Krsmanovic, Jan Valecka, Kamila Chramostová, Vojtech Kulvait, Jiri Zavadil, Martin Vokurka, Peter Laslo, and Tomas Stopka. "Graded PU.1 Levels Regulate Granulocyte Vs. Macrophage Genes Via Multiple Enhancer Elements." Blood 128, no. 22 (December 2, 2016): 403. http://dx.doi.org/10.1182/blood.v128.22.403.403.
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Abstract PU.1 is a transcription factor absolutely required for normal hematopoiesis. Cumulating evidence indicates that precise levels of PU.1 expression are critical for differentiation to distinct blood lineages, and if perturbed, even modest decreases in PU.1 can lead to leukemogenesis. In contrast to extensive knowledge of regulation of PU.1 gene itself, the mechanism of how target genes senses different PU.1 levels remain largely unknown. To address this, we used PU.1-/- mouse myeloid progenitors encoding inducible PU.1 transgene (PU.1ER, PUER, Walsh 2002) that allows tight control of PU.1 activity. Interestingly, intermediate PU.1 activity induced differentiation of PUER progenitors into granulocyte like cells, while high PU.1 produced macrophages, supporting the model that different PU.1 expression is not a consequence but a driver of cell fate choice. Global expression analysis using 4 different levels of PU.1 at 8 time points (2-96 hrs) revealed that granulocyte specific genes were activated exclusively by intermediate PU.1 levels in 3 distinct modes: 1. not expressed in progenitors while strongly induced at intermediate PU.1 (e.g. Gelatinase B (Mmp9) and Neutrophil collagenase (NC) 2. moderately expressed in progenitors while strongly activated at intermediate PU.1 and repressed at high PU.1 (e.g. Myeloperaxidase (Mpo) 3. highly expressed in unstimulated progenitors with expression maintained at intermediate PU.1 but strongly repressed at high PU.1 (e.g. Neutrophil elastase (NE), Proteinase 3 (primary granule proteins), Cebpe and Gfi1 (Growth factor independent1) Majority of macrophage genes (incl. CD14, Csf1R, Egr2) were regulated as early PU.1 target genes; being gradually activated by high PU.1 activity within 8hrs. However, most granulocyte genes (NE, Mmp9, Mpo, NC but not Cebpe and GFI1) were late activated PU.1 targets (48 and 96hrs) indicating that these genes are coregulated by additional factor(s), likely an early PU.1 target. Next we analyzed the regulatory sequences (+-50kb) of two genes activated exclusively by intermediate PU.1, Mpo and Mmp9, using own and public ChIP(seq) data of transcription factors (TFs) (PU.1, GFI.1), DNAseI hypersensitive sites, histone modifications (H3K4Me, H3K27Ac, H3K9Ac) and expression of enhancer specific bidirectional ncRNAs (eRNA) (CAGE). 14 Mpo and 16 Mmp9 putative enhancers, selected by above mentioned criteria, were cloned into luciferase vector containing their proximal promoter (PP) and were tested for functional activity in response to PU.1 levels. Interestingly, the PU.1 binding motifs within these regions have a low to intermediate affinity (log of score, Jaspar) and are often present in multiples and/or enriched for binding sites of other lineage determining transcription factors. Although PU.1 bound to all of these DNA regions resembling superenhancer, just a small fraction of PU.1 binding was functionally responsive. Specifically, we identified novel enhancer elements at -3.4 kb and -15kb of MPO which were activated by intermediate (but not high) PU.1 levels. Interestingly, activity of -3.4 kb enhancer required presence of PP, while the -15kb element required presence of both PP and the -3.4kb element. Similar phenomenon was observed at -5kb and +4.6kb (intronic) MMP9 enhancers. Collectively, these observations suggest that a cooperative assembly of several cell type-specific enhancers is required for optimal Mpo and Mmp9 activation. This model is supported by our Chromosome conformation capture (3C) data identifying 3D interaction of these enhancer elements at intermediate PU.1 levels suggesting that PU.1 binding mediates DNA looping that allows enhancer cooperation. In addition, activity of these enhancers at intermediate PU.1 levels was associated with expression of bidirectional noncoding enhancer RNAs, confirming functionality of these elements. In conclusion, our data support the model that PU.1 at intermediate concentration binds to low and intermediate affinity binding sites in several enhancers of granulocyte genes, causing their successive looping and interaction with proximal promoter that leads to transcription activation. The role of cooperating TFs, mechanisms of how granulocyte genes are switched off at high PU.1 concentration and deregulation of these mechanisms in AML are being further studied. Grants 16-05649S P305/12/1033 16-31586A 16-27790A 16-31586A UNCE 204021 PRVOUK P24 Disclosures No relevant conflicts of interest to declare.
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He, Daniel, David Wu, Soren Muller, Lin Wang, Parna Saha, Sajad Hamid Ahanger, Siyuan John Liu, et al. "miRNA-independent function of long noncoding pri-miRNA loci." Proceedings of the National Academy of Sciences 118, no. 13 (March 23, 2021): e2017562118. http://dx.doi.org/10.1073/pnas.2017562118.
Full textAbstract:
Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1–independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.
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Liu, Eric Minwei, Alexander Martinez-Fundichely, Rajesh Bollapragada, Maurice Spiewack, and Ekta Khurana. "CNCDatabase: a database of non-coding cancer drivers." Nucleic Acids Research 49, no. D1 (October 23, 2020): D1094—D1101. http://dx.doi.org/10.1093/nar/gkaa915.
Full textAbstract:
Abstract Most mutations in cancer genomes occur in the non-coding regions with unknown impact on tumor development. Although the increase in the number of cancer whole-genome sequences has revealed numerous putative non-coding cancer drivers, their information is dispersed across multiple studies making it difficult to understand their roles in tumorigenesis of different cancer types. We have developed CNCDatabase, Cornell Non-coding Cancer driver Database (https://cncdatabase.med.cornell.edu/) that contains detailed information about predicted non-coding drivers at gene promoters, 5′ and 3′ UTRs (untranslated regions), enhancers, CTCF insulators and non-coding RNAs. CNCDatabase documents 1111 protein-coding genes and 90 non-coding RNAs with reported drivers in their non-coding regions from 32 cancer types by computational predictions of positive selection using whole-genome sequences; differential gene expression in samples with and without mutations; or another set of experimental validations including luciferase reporter assays and genome editing. The database can be easily modified and scaled as lists of non-coding drivers are revised in the community with larger whole-genome sequencing studies, CRISPR screens and further experimental validations. Overall, CNCDatabase provides a helpful resource for researchers to explore the pathological role of non-coding alterations in human cancers.
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Rusconi, Francesco, Elena Battaglioli, and Marco Venturin. "Psychiatric Disorders and lncRNAs: A Synaptic Match." International Journal of Molecular Sciences 21, no. 9 (April 25, 2020): 3030. http://dx.doi.org/10.3390/ijms21093030.
Full textAbstract:
Psychiatric disorders represent a heterogeneous class of multifactorial mental diseases whose origin entails a pathogenic integration of genetic and environmental influences. Incidence of these pathologies is dangerously high, as more than 20% of the Western population is affected. Despite the diverse origins of specific molecular dysfunctions, these pathologies entail disruption of fine synaptic regulation, which is fundamental to behavioral adaptation to the environment. The synapses, as functional units of cognition, represent major evolutionary targets. Consistently, fine synaptic tuning occurs at several levels, involving a novel class of molecular regulators known as long non-coding RNAs (lncRNAs). Non-coding RNAs operate mainly in mammals as epigenetic modifiers and enhancers of proteome diversity. The prominent evolutionary expansion of the gene number of lncRNAs in mammals, particularly in primates and humans, and their preferential neuronal expression does represent a driving force that enhanced the layering of synaptic control mechanisms. In the last few years, remarkable alterations of the expression of lncRNAs have been reported in psychiatric conditions such as schizophrenia, autism, and depression, suggesting unprecedented mechanistic insights into disruption of fine synaptic tuning underlying severe behavioral manifestations of psychosis. In this review, we integrate literature data from rodent pathological models and human evidence that proposes the biology of lncRNAs as a promising field of neuropsychiatric investigation.
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Shyamsunder, Pavithra, Shree Pooja Sridharan, Pushkar Dakle, Zeya Cao, Vikas Madan, Sin Tiong Ong, and H. Phillip Koeffler. "PML-RAR Binds to the +7kb Enhancer of CEBPE and Inhibits Its Expression." Blood 136, Supplement 1 (November 5, 2020): 43. http://dx.doi.org/10.1182/blood-2020-136230.
Full textAbstract:
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The disease is identified by distinctive morphology and is distinguished by a balanced reciprocal translocation between chromosomes 15 and 17. This aberration leads to the fusion between promyelocytic leukemia (PML) gene located on chromosome 15q21, and retinoic acid receptor α (RARA) gene from chromosome 17q21, leading to the resultant chimeric onco-fusion protein PML-RARA, which is detectable in more than 95% patients and disturbs proper promyelocytic differentiation. All-trans retinoic acid (ATRA) can induce granulocytic differentiation in APL and is used to treat APL patients. Genes containing PML-RARA-targeted promoters are transcriptionally suppressed in APL and most likely constitute a major mechanism of transcriptional repression occurring in APL. A growing body of evidence points to the role of distal regulatory elements, including enhancers, in the control of gene expression. In order to understand the unique sets of enhancers that might be under the control of PML-RAR and crucial for granulocytic differentiation of NB4 cells, we analysed the enhancer landscape of control and ATRA treated NB4 cells. H3K9Ac mapping identified a repertoire of enhancers that were gained in NB4 cells treated with ATRA. Closer investigation of these enhancer elements revealed enrichment of H3K9Ac signals around major drivers of myeloid differentiation. Of note, we identified a gain in enhancer signature for a region about 7kb downstream of the CEBPE gene. Our previous studies identified a novel enhancer for CEBPE in murine hematopoietic cells, which was 6 downstream of CEBPE core promoter. It appears that the +7kb region we identified in human APL cells may be analogous to the murine enhancer. We also observed that PML-RAR binds this +7kb region and ATRA treatment of NB4 cells displaced binding of PML-RAR from the + 7kb region, suggestive of a transcriptional repressive effect of PML-RAR at such enhancer elements. To test the transcription regulating potential of this +7kb region, we used catalytically inactive Cas9 fused to Krüppel associated box (KRAB) domain (dCas9-KRAB). We designed three guide RNAs covering this regulatory region. The sgRNAs effectively repressed expression of CEBPE accompanied by lowered granulocytic differentiation of these guide RNA targeted NB4 cells after ATRA treatment. To explore transcription factor (TF) occupancy at this +7 kb region, we analysed public available ChIP-seq datasets for hematopoiesis-specific factors. Analysis revealed that the +7kb region was marked by an open chromatin signature, accompanied by binding of a majority of hematopoietic TFs around this putative regulatory element with concurrent binding of EP300. Strikingly we noticed binding of CEBPA, CEBPB and CEBPE at this regulatory element. To assess whether binding of these members of the CEBP family of TFs is functionally relevant, luciferase reporter and electrophoretic mobility shift assays (EMSA) were performed. Co expression of the CEBP TFs led to significant induction of luciferase expression, and this data was further confirmed using EMSA assays. Based on these observations, we propose that PML-RAR blocks granulocytic differentiation by occupying this +7kb enhancer of CEBPE, hinders binding of other cell type/lineage specific TFs, and blocks CEBPE expression. When cells are stimulated with ATRA, PML-RAR is displaced from the CEBPE enhancer, allowing for efficient binding of myeloid-specific TFs. This results in increased CEBPE expression, which in turn promotes efficient granulocytic differentiation. The findings from our study expands our current understanding of the mechanism of differentiation therapy, the role of onco-fusion proteins in inhibiting myeloid differentiation, and may provide new therapeutic approaches to many acute myeloid leukemias. Disclosures Ong: National University of Singapore: Other: Royalties.