Journal articles: 'Jumonji Domain-Containing Histone Demethylases'

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Leon, Kelly E., and Katherine M. Aird. "Jumonji C Demethylases in Cellular Senescence." Genes 10, no. 1 (January 9, 2019): 33. http://dx.doi.org/10.3390/genes10010033.

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Senescence is a stable cell cycle arrest that is either tumor suppressive or tumor promoting depending on context. Epigenetic changes such as histone methylation are known to affect both the induction and suppression of senescence by altering expression of genes that regulate the cell cycle and the senescence-associated secretory phenotype. A conserved group of proteins containing a Jumonji C (JmjC) domain alter chromatin state, and therefore gene expression, by demethylating histones. Here, we will discuss what is currently known about JmjC demethylases in the induction of senescence, and how these enzymes suppress senescence to contribute to tumorigenesis.

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Liu, Haolin, Chao Wang, Schuyler Lee, Yu Deng, Matthew Wither, Sangphil Oh, Fangkun Ning, et al. "Clipping of arginine-methylated histone tails by JMJD5 and JMJD7." Proceedings of the National Academy of Sciences 114, no. 37 (August 28, 2017): E7717—E7726. http://dx.doi.org/10.1073/pnas.1706831114.

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Two of the unsolved, important questions about epigenetics are: do histone arginine demethylases exist, and is the removal of histone tails by proteolysis a major epigenetic modification process? Here, we report that two orphan Jumonji C domain (JmjC)-containing proteins, JMJD5 and JMJD7, have divalent cation-dependent protease activities that preferentially cleave the tails of histones 2, 3, or 4 containing methylated arginines. After the initial specific cleavage, JMJD5 and JMJD7, acting as aminopeptidases, progressively digest the C-terminal products. JMJD5-deficient fibroblasts exhibit dramatically increased levels of methylated arginines and histones. Furthermore, depletion of JMJD7 in breast cancer cells greatly decreases cell proliferation. The protease activities of JMJD5 and JMJD7 represent a mechanism for removal of histone tails bearing methylated arginine residues and define a potential mechanism of transcription regulation.

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Pollard, Patrick J., Christoph Loenarz, David R. Mole, Michael A. McDonough, Jonathan M. Gleadle, Christopher J. Schofield, and Peter J. Ratcliffe. "Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α." Biochemical Journal 416, no. 3 (November 26, 2008): 387–94. http://dx.doi.org/10.1042/bj20081238.

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The transcription factor HIF (hypoxia-inducible factor) mediates a highly pleiotrophic response to hypoxia. Many recent studies have focused on defining the extent of this transcriptional response. In the present study we have analysed regulation by hypoxia among transcripts encoding human Fe(II)- and 2-oxoglutarate-dependent oxygenases. Our results show that many of these genes are regulated by hypoxia and define two groups of histone demethylases as new classes of hypoxia-regulated genes. Patterns of induction were consistent across a range of cell lines with JMJD1A (where JMJD is Jumonji-domain containing) and JMJD2B demonstrating robust, and JMJD2C more modest, up-regulation by hypoxia. Functional genetic and chromatin immunoprecipitation studies demonstrated the importance of HIF-1α in mediating these responses. Given the importance of histone methylation status in defining patterns of gene expression under different physiological and pathophysiological conditions, these findings predict a role for the HIF system in epigenetic regulation.

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Cui, Xiaoyun, Yu Zheng, Yue Lu, Emmanuelle Issakidis-Bourguet, and Dao-Xiu Zhou. "Metabolic control of histone demethylase activity involved in plant response to high temperature." Plant Physiology 185, no. 4 (January 28, 2021): 1813–28. http://dx.doi.org/10.1093/plphys/kiab020.

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Abstract Jumonji C (JmjC) domain proteins are histone lysine demethylases that require ferrous iron and alpha-ketoglutarate (or α-KG) as cofactors in the oxidative demethylation reaction. In plants, α-KG is produced by isocitrate dehydrogenases (ICDHs) in different metabolic pathways. It remains unclear whether fluctuation of α-KG levels affects JmjC demethylase activity and epigenetic regulation of plant gene expression. In this work, we studied the impact of loss of function of the cytosolic ICDH (cICDH) gene on the function of histone demethylases in Arabidopsis thaliana. Loss of cICDH resulted in increases of overall histone H3 lysine 4 trimethylation (H3K4me3) and enhanced mutation defects of the H3K4me3 demethylase gene JMJ14. Genetic analysis suggested that the cICDH mutation may affect the activity of other demethylases, including JMJ15 and JMJ18 that function redundantly with JMJ14 in the plant thermosensory response. Furthermore, we show that mutation of JMJ14 affected both the gene activation and repression programs of the plant thermosensory response and that JMJ14 and JMJ15 repressed a set of genes that are likely to play negative roles in the process. The results provide evidence that histone H3K4 demethylases are involved in the plant response to elevated ambient temperature.

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Hickok, Jason R., Divya Vasudevan, William E. Antholine, and Douglas D. Thomas. "Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases." Journal of Biological Chemistry 288, no. 22 (April 1, 2013): 16004–15. http://dx.doi.org/10.1074/jbc.m112.432294.

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Hickok, Jason R., Divya Vasudevan, and Douglas D. Thomas. "Nitric Oxide Modifies Histone Methylation Patterns by Inhibiting Jumonji C Domain Containing Demethylases." Free Radical Biology and Medicine 53 (November 2012): S181. http://dx.doi.org/10.1016/j.freeradbiomed.2012.10.499.

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Chopra, Anand, Hemanta Adhikary, William G. Willmore, and Kyle K. Biggar. "Insights into The Function and Regulation of Jumonji C Lysine Demethylases as Hypoxic Responsive Enzymes." Current Protein & Peptide Science 21, no. 7 (September 23, 2020): 642–54. http://dx.doi.org/10.2174/1389203721666191231104225.

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Cellular responses to hypoxia (low oxygen) are governed by oxygen sensitive signaling pathways. Such pathways, in part, are controlled by enzymes with oxygen-dependent catalytic activity, of which the role of prolyl 4-hydroxylases has been widely reviewed. These enzymes inhibit hypoxic response by inducing the oxygen-dependent degradation of hypoxia-inducible factor 1α, the master regulator of the transcriptional hypoxic response. Jumonji C domain-containing lysine demethylases are similar enzymes which share the same oxygen-dependent catalytic mechanism as prolyl 4- hydroxylases. Traditionally, the role of lysine demethylases has been studied in relation to demethylation activity against histone substrates, however, within the past decade an increasing number of nonhistone protein targets have been revealed, some of which have a key role in survival in the hypoxic tumor microenvironment. Within this review, we highlight the involvement of methyllysine in the hypoxic response with a focus on the HIF signaling pathway, the regulation of demethylase activity by oxygen, and provide insights into notable areas of future hypoxic demethylase research.

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Xu, Xin, Wilhelm G. Dirks, Hans G. Drexler, and Zhenbo Hu. "Small Molecular Modulators of Histone Demethylases Selectively Inhibits Growth of Hematopoietic Malignancies." Blood 132, Supplement 1 (November 29, 2018): 3941. http://dx.doi.org/10.1182/blood-2018-99-112376.

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Abstract Background: About 10% of acute leukemia (AL) patients harbor MLL-r(earrangements). MLLr acute myeloid leukemia (AML) mainly occurs in young-to-middle-aged adults whereas MLLr acute lymphoblastic leukemia (ALL) mainly occurs in patients younger than 1 year at diagnosis. AML with MLL fusion to MLLT3 via t(9;11)(p22;q23) predicts intermediate prognosis whereas MLL fusion to other partners predicts adverse prognosis. By contrast, in infants with ALL MLLr invariably confers poor prognosis. Much efforts have been made to identify and target proteins required for initiation and maintenance of MLLr AL, with an aim to improve the prognosis of this aggressive AL subtype. Multiple writers, erasers, and readers of histone post-translational modifications (PTMs) have been identified to be fundamental for the initiation and maintenance of MLLr AL. Small molecular inhibitors of some of these chromatin-associated proteins have been identified, such as EPZ004777 against DOT1L, JQ1 and I-BET151 against BRD4, and so on which are also under clinical trials for AL treatment. Among histone modification erasers essential for MLLr AL, JMJD1C and KDM4C that share Jumonji catalytic domain are fundamental for MLLr AL maintenance. Histone H3 lysine 9 (H3K9) demethylase JMJD1C is one of the most promising MLLr AL targets. Multiple independent studies identified JMJD1C as required for MLLr AML, RUNX1(AML1)/RUNX1T1(ETO) AML and even chronic myeloid leukemia and lymphoma cells but not normal hematopoiesis. KDM4C Is essential for Initiation and maintenance of MLLr AL transcriptional profiling of which is dependent on KDM4C. Moreover, pharmacological inhibition of KDM4C blocks leukemia development in syngeneic mouse model and human AML xenograft model. Although a large number of special inhibitors of histone demethylases have been developed, no special inhibitors against KDM3 family member like JMJD1C have been reported. Results: Here we focused on Jumonji domain that is responsible for enzymatic activities of histone demethylases for identifying potential small molecule modulators of histone demethylases. We selected Jumonji domain of histone H3 lysine (H3K9) demethylase JMJD1C with KDM4C as reference to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components through virtual screening method. Although identified independently from each other, compound #4 and #12 both share a common structural backbone and surface plasmon resonance analysis showed that #4 and #12 bind to JMJD1C, KDM3 family member KDM3B, and KDM4 family member KDM4C with modest affinity. In vivo demethylation assay showed that #4 induces global increase of H3K9 methylation. In vitro demethylation assay showed that #4 is able to reverse H3K9 demethylation conferred by KDM3B and KDM4C. We thus named #4 and #12 as JI-4 and JI-12 (JI, Jumonji inhibitor). Cell proliferation and colony formation assays showed that JI-4 and JI-12 predominantly kill MLLr AL. To increase evidence, multiple similar compounds to JI-4 and JI-12 were tested for cell proliferation repression and JI-16 was found to show superior killing activities against hematopoietic malignant cells compared to JI-4 and JI-12. Mechanistically, JI-16 not only induces apoptosis but also differentiation of MLLr AL cells. Transcriptome analysis and quantitative PCR (QPCR) showed that JI-16 induced gene expression profiling is especially enriched in gene sets involved in metabolism. Conclusion: To sum up, we identified potential pan-inhibitors of the Jumonji domain of histone demethylases. Binding in-vivo is followed by selective killing of MLLr AL cells. Disclosures. No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

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Hastar, N., D. Koca, and Y. Baran. "PP-074 INHIBITION OF JUMONJI C DOMAIN CONTAINING HISTONE DEMETHYLASES IN ACUTE MYELOID LEUKEMIA." Leukemia Research 38 (October 2014): S50. http://dx.doi.org/10.1016/s0145-2126(14)70128-6.

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Cho, Yumi, Ki Hyun Kim, Yoon Sun Cho, Wenqing Xu, Xiang Wang, and Ho Jeong Kwon. "A histone demethylase inhibitor, methylstat, inhibits angiogenesis in vitro and in vivo." RSC Adv. 4, no. 72 (2014): 38230–33. http://dx.doi.org/10.1039/c4ra07154a.

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Histone methylation has been highlighted in the regulation of gene expression. Methylstat, a Jumonji C domain containing histone demethylase inhibitor, inhibitedin vitroandin vivoangiogenesis at nontoxic dose. Collectively, methylstat could be a promising chemical probe for addressing its role in angiogenesis

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Yoo, Jung, Yu Hyun Jeon, Ha Young Cho, Sang Wu Lee, Go Woon Kim, Dong Hoon Lee, and So Hee Kwon. "Advances in Histone Demethylase KDM3A as a Cancer Therapeutic Target." Cancers 12, no. 5 (April 28, 2020): 1098. http://dx.doi.org/10.3390/cancers12051098.

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Lysine-specific histone demethylase 3 (KDM3) subfamily proteins are H3K9me2/me1 histone demethylases that promote gene expression. The KDM3 subfamily primarily consists of four proteins (KDM3A−D). All four proteins contain the catalytic Jumonji C domain (JmjC) at their C-termini, but whether KDM3C has demethylase activity is under debate. In addition, KDM3 proteins contain a zinc-finger domain for DNA binding and an LXXLL motif for interacting with nuclear receptors. Of the KDM3 proteins, KDM3A is especially deregulated or overexpressed in multiple cancers, making it a potential cancer therapeutic target. However, no KDM3A-selective inhibitors have been identified to date because of the lack of structural information. Uncovering the distinct physiological and pathological functions of KDM3A and their structure will give insight into the development of novel selective inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM3A in cancer. We also discuss existing KDM3A-related inhibitors and review their potential as therapeutic agents for overcoming cancer.

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Chang, Yuanyuan, Jian Wu, Xia-Jing Tong, Jin-Qiu Zhou, and Jianping Ding. "Crystal structure of the catalytic core of Saccharomyces cerevesiae histone demethylase Rph1: insights into the substrate specificity and catalytic mechanism." Biochemical Journal 433, no. 2 (December 22, 2010): 295–302. http://dx.doi.org/10.1042/bj20101418.

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Saccharomyces cerevesiae Rph1 is a histone demethylase orthologous to human JMJD2A (Jumonji-domain-containing protein 2A) that can specifically demethylate tri- and di-methylated Lys36 of histone H3. c-Rph1, the catalytic core of Rph1, is responsible for the demethylase activity, which is essential for the transcription elongation of some actively transcribed genes. In the present work, we report the crystal structures of c-Rph1 in apo form and in complex with Ni2+ and α-KG [2-oxoglutarate (α-ketoglutarate)]. The structure of c-Rph1 is composed of a JmjN (Jumonji N) domain, a long β-hairpin, a mixed structural motif and a JmjC domain. The α-KG cofactor forms hydrogen-bonding interactions with the side chains of conserved residues, and the Ni2+ ion at the active site is chelated by conserved residues and the cofactor. Structural comparison of Rph1 with JMJD2A indicates that the substrate-binding cleft of Rph1 is formed with several structural elements of the JmjC domain, the long β-hairpin and the mixed structural motif; and the methylated Lys36 of H3 is recognized by several conserved residues of the JmjC domain. In vitro biochemical results show that mutations of the key residues at the catalytic centre and in the substrate-binding cleft abolish the demethylase activity. In vivo growth phenotype analyses also demonstrate that these residues are essential for its functional roles in transcription elongation. Taken together, our structural and biological data provide insights into the molecular basis of the histone demethylase activity and the substrate specificity of Rph1.

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Luo, Xuelai, Yongxiang Liu, Stefan Kubicek, Johanna Myllyharju, Anthony Tumber, Stanley Ng, Ka Hing Che, et al. "A Selective Inhibitor and Probe of the Cellular Functions of Jumonji C Domain-Containing Histone Demethylases." Journal of the American Chemical Society 133, no. 24 (June 22, 2011): 9451–56. http://dx.doi.org/10.1021/ja201597b.

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Yu, Violeta, Tanja Fisch, Alexander M. Long, Jin Tang, Josie Han Lee, Markus Hierl, Hao Chen, Peter Yakowec, Ralf Schwandner, and Renee Emkey. "High-Throughput TR-FRET Assays for Identifying Inhibitors of LSD1 and JMJD2C Histone Lysine Demethylases." Journal of Biomolecular Screening 17, no. 1 (August 21, 2011): 27–38. http://dx.doi.org/10.1177/1087057111418228.

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Lysine demethylase 1 (LSD1) and Jumonji C domain–containing oxygenase D2C (JMJD2C) participate in regulating the methylation status of histone H3 lysine residues. In some contexts, LSD1 and JMJD2C activity causes enhanced cellular proliferation, which may lead to tumorigenesis. The authors explored the utility of time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassays, which employed peptides consisting of the first 21 amino acids of histone H3 in which lysine 4 (H3K4) or lysine 9 (H3K9) was methylated (me) to quantify LSD1 and JMJD2C activity. The LSD1 assay monitored demethylation of the H3K4me1 peptide using an antibody that recognizes H3K4me1 but not the unmethylated peptide product. The JMJD2C assay measured demethylation of H3K9me3 with an antibody that selectively recognizes H3K9me2. The optimized conditions resulted in robust assays (Z′ > 0.7) that required only 3 to 6 nM of enzyme in a reaction volume of 6 to 10 µL. These assays were used to compare the activity of different LSD1 constructs and to determine the apparent Km of each JMJD2C substrate. Finally, both assays were used in a high-throughput setting for identifying demethylase inhibitors. Compounds discovered by these TR-FRET methods may lead to powerful tools for ascertaining the roles of demethylases in a cellular context and ultimately for potential cancer treatments.

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Wang, Wei, Laura J. Marholz, and Xiang Wang. "Novel Scaffolds of Cell-Active Histone Demethylase Inhibitors Identified from High-Throughput Screening." Journal of Biomolecular Screening 20, no. 6 (April 16, 2015): 821–27. http://dx.doi.org/10.1177/1087057115579637.

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Jumonji C domain-containing histone demethylases (JHDMs) are epigenetic proteins capable of demethylating methylated lysine residues on histones proteins and for which high-quality chemical probes and eventual therapeutic leads are highly desirable. To expand the extent of known scaffolds targeting JHDMs, we initiated an unbiased high-throughput screening approach using a fluorescence polarization (FP)–based competitive binding assay we recently reported for JHDM1A (aka KDM2A). In total, 14,400 compounds in the HitFinder collection v.11 were screened, which represent all the distinct skeletons of the Maybridge Library. An eventual three compounds with two new scaffolds were discovered and further validated, which not only show in vitro binding for two different JHDMs, JHDM1A and JMJD2A (aka KDM4A), but also induce hypermethylation of their substrate in cells. These represent novel scaffolds as JHDM inhibitors and provide a basis for future optimization of affinity and selectivity.

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Bergmann, Christina, Amelie Brandt, Benita Merlevede, Ludwig Hallenberger, Clara Dees, Thomas Wohlfahrt, Sebastian Pötter, et al. "The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis." Annals of the Rheumatic Diseases 77, no. 1 (October 25, 2017): 150–58. http://dx.doi.org/10.1136/annrheumdis-2017-211501.

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ObjectivesSystemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.MethodsJMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.ResultsThe expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGFβ)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGFβ. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.ConclusionWe present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.

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Yamaguchi, Nobutoshi, and Toshiro Ito. "JMJ Histone Demethylases Balance H3K27me3 and H3K4me3 Levels at the HSP21 Locus during Heat Acclimation in Arabidopsis." Biomolecules 11, no. 6 (June 7, 2021): 852. http://dx.doi.org/10.3390/biom11060852.

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Exposure to moderately high temperature enables plants to acquire thermotolerance to high temperatures that might otherwise be lethal. In Arabidopsis thaliana, histone H3 lysine 27 trimethylation (H3K27me3) at the heat shock protein 17.6C (HSP17.6C) and HSP22 loci is removed by Jumonji C domain-containing protein (JMJ) histone demethylases, thus allowing the plant to ‘remember’ the heat experience. Other heat memory genes, such as HSP21, are downregulated in acclimatized jmj quadruple mutants compared to the wild type, but how those genes are regulated remains uncharacterized. Here, we show that histone H3 lysine 4 trimethylation (H3K4me3) at HSP21 was maintained at high levels for at least three days in response to heat. This heat-dependent H3K4me3 accumulation was compromised in the acclimatized jmj quadruple mutant as compared to the acclimatized wild type. JMJ30 directly bound to the HSP21 locus in response to heat and coordinated H3K27me3 and H3K4me3 levels under standard and fluctuating conditions. Our results suggest that JMJs mediate the balance between H3K27me3 and H3K4me3 at the HSP21 locus through proper maintenance of H3K27me3 removal during heat acclimation.

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Zhang, Xiangxian, Li Liu, Xia Yuan, Yuquan Wei, and Xiawei Wei. "JMJD3 in the regulation of human diseases." Protein & Cell 10, no. 12 (November 7, 2019): 864–82. http://dx.doi.org/10.1007/s13238-019-0653-9.

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ABSTRACT In recent years, many studies have shown that histone methylation plays an important role in maintaining the active and silent state of gene expression in human diseases. The Jumonji domain-containing protein D3 (JMJD3), specifically demethylate di- and trimethyl-lysine 27 on histone H3 (H3K27me2/3), has been widely studied in immune diseases, infectious diseases, cancer, developmental diseases, and aging related diseases. We will focus on the recent advances of JMJD3 function in human diseases, and looks ahead to the future of JMJD3 gene research in this review.

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Quan, Zhenzhen, Stephen G. Oliver, and Nianshu Zhang. "JmjN interacts with JmjC to ensure selective proteolysis of Gis1 by the proteasome." Microbiology 157, no. 9 (September 1, 2011): 2694–701. http://dx.doi.org/10.1099/mic.0.048199-0.

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A group of JmjC domain-containing proteins also harbour JmjN domains. Although the JmjC domain is known to possess histone demethylase activity, the function of the JmjN domain remains largely undetermined. Previously, we have demonstrated that the yeast Gis1 transcription factor, bearing both JmjN and JmjC domains at its N terminus, is subject to proteasome-mediated selective proteolysis to downregulate its transcription activation ability. Here, we reveal that the JmjN and JmjC domains interact with each other through two β-sheets, one in each domain. Removal of either or both β-strands or the entire JmjN domain leads to complete degradation of Gis1, mediated partially by the proteasome. Mutating the core residues essential for histone demethylase activity demonstrated for other JmjC-containing proteins or deleting both Jumonji domains enhances the transcription activity of Gis1, but has no impact on its selective proteolysis by the proteasome. Together, these data suggest that JmjN and JmjC interact physically to form a structural unit that ensures the stability and appropriate transcription activity of Gis1.

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Sanchez, Anna, Fatma Zohra Houfaf Khoufaf, Mouhamed Idrissou, Frédérique Penault-Llorca, Yves-Jean Bignon, Laurent Guy, and Dominique Bernard-Gallon. "The Functions of the Demethylase JMJD3 in Cancer." International Journal of Molecular Sciences 22, no. 2 (January 19, 2021): 968. http://dx.doi.org/10.3390/ijms22020968.

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Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3’s involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.

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Gao, Wei-wei, Rong-quan Xiao, Bing-ling Peng, Huan-teng Xu, Hai-feng Shen, Ming-feng Huang, Tao-tao Shi, et al. "Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation." Proceedings of the National Academy of Sciences 112, no. 26 (June 16, 2015): E3327—E3336. http://dx.doi.org/10.1073/pnas.1509658112.

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Although “histone” methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conserved arginine residue, R469, in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily conserved protein family of ATP-dependent molecular chaperone, was monomethylated (me1), at least partially, by coactivator-associated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonji-domain–containing 6 (JMJD6), both in vitro and in cultured cells. Functional studies revealed that HSP70 could directly regulate retinoid acid (RA)-induced retinoid acid receptor β2 (RARβ2) gene transcription through its binding to chromatin, with R469me1 being essential in this process. HSP70’s function in gene transcriptional regulation appears to be distinct from its protein chaperon activity. R469me1 was shown to mediate the interaction between HSP70 and TFIIH, which involves in RNA polymerase II phosphorylation and thus transcriptional initiation. Our findings expand the repertoire of nonhistone substrates targeted by PRMT4 and JMJD6, and reveal a new function of HSP70 proteins in gene transcription at the chromatin level aside from its classic role in protein folding and quality control.

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Garcia, Jeison, and Fernando Lizcano. "KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer." Breast Cancer: Basic and Clinical Research 10 (January 2016): BCBCR.S40182. http://dx.doi.org/10.4137/bcbcr.s40182.

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The Jumonji-containing domain protein, KDM4C, is a histone demethylase associated with the development of several forms of human cancer. However, its specific function in the viability of tumoral lineages is yet to be determined. This work investigates the importance of KDM4C activity in cell proliferation and chromosome segregation of three triple-negative breast cancer cell lines using a specific demethylase inhibitor. Immunofluorescence assays show that KDM4C is recruited to mitotic chromosomes and that the modulation of its activity increases the number of mitotic segregation errors. However, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell proliferation assays demonstrate that the demethylase activity is required for cell viability. These results suggest that the histone demethylase activity of KDM4C is essential for breast cancer progression given its role in the maintenance of chromosomal stability and cell growth, thus highlighting it as a potential therapeutic target.

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Deleris, Angelique, Maxim V. C. Greenberg, Israel Ausin, Rona W. Y. Law, Guillaume Moissiard, Daniel Schubert, and Steven E. Jacobsen. "Involvement of a Jumonji‐C domain‐containing histone demethylase in DRM2‐mediated maintenance of DNA methylation." EMBO reports 11, no. 12 (November 5, 2010): 950–55. http://dx.doi.org/10.1038/embor.2010.158.

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Lee, Ho-Youl, Eun Gyeong Yang, and Hyunsung Park. "Hypoxia enhances the expression of prostate-specific antigen by modifying the quantity and catalytic activity of Jumonji C domain-containing histone demethylases." Carcinogenesis 34, no. 12 (July 24, 2013): 2706–15. http://dx.doi.org/10.1093/carcin/bgt256.

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Horton, John R., Amanda Engstrom, Elizabeth L. Zoeller, Xu Liu, John R. Shanks, Xing Zhang, Margaret A. Johns, Paula M. Vertino, Haian Fu, and Xiaodong Cheng. "Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases." Journal of Biological Chemistry 291, no. 6 (December 8, 2015): 2631–46. http://dx.doi.org/10.1074/jbc.m115.698449.

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Roatsch, Martin, Inga Hoffmann, Martine I. Abboud, Rebecca L. Hancock, Hanna Tarhonskaya, Kuo-Feng Hsu, Sarah E. Wilkins, et al. "The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases." ACS Chemical Biology 14, no. 8 (July 9, 2019): 1737–50. http://dx.doi.org/10.1021/acschembio.9b00289.

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Alberro, Nerea, Miquel Torrent-Sucarrat, Iosune Arrastia, Ana Arrieta, and Fernando P. Cossío. "Two-State Reactivity of Histone Demethylases Containing Jumonji-C Active Sites: Different Mechanisms for Different Methylation Degrees." Chemistry - A European Journal 23, no. 1 (November 23, 2016): 137–48. http://dx.doi.org/10.1002/chem.201604219.

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Korczynska, Magdalena, Daniel Le, Elisabet Gregori-Puigjané, Noah Younger, Tobias Krojer, Anthony Tumber, Udo Oppermann, Danica Galonić Fujimori, and Brian Shoichet. "Virtual Screening of Histone Lysine Demethylase(JMJD2) identifies new inhibitors." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C820. http://dx.doi.org/10.1107/s2053273314091797.

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The JmjC domain-containing proteins are hydroxylases that confer posttranslational modifications on histone tails, by removing methylation marks on methylated lysine residues. This serves to either promote or repress gene transcription. The JMJD2A-D family members include the enzyme Jumonji domain 2C (JMJD2C), which specifically demethylates di- and trimethylated histone H3 at Lys 9 or Lys 36.[1] Dysregulation of JMJD2C has been implicated in prostate, colonic, and breast cancer as the demethylase can modify the expression levels of oncogenes.[2] The goal of the present study was to identify potent and selective small-molecule inhibitors of JMJD2C, to be used as chemical biology tools to further investigate the role of JMJD2C in cell proliferation and survival. Using high-resolution crystal structures of the JMJD2 subfamily members as templates, we have performed a small molecule virtual docking screen. From the ~3 million molecules that were docked, this experiment identified 21 compounds as possible leads. These compounds were tested against JMJD2C in enzymatic assays and here we report an overall hit rate of 76%, with 8 compounds demonstrating an IC50 of 176μM to 1.18μM. A molecule containing a salicylate core was selected as a candidate for optimization and thus far we have completed several rounds of iterative target-specific compound docking, hybrid molecule design, compound synthesis and in vitro characterization. Notably, our method demonstrated a substantial increase in potency when we linked two docked fragments together and further derivatized this new scaffold, through which we have successfully derived a 65nM inhibitor of JMJD2C. A compound representing the inhibitor scaffold has been co-crystallized with JMJD2A to a resolution of 2.4 Å. In the crystal structure each asymmetric unit contains two JMJD2A monomers, each bound to a single inhibitor molecule. This complex-structure superposes well with the docked pose for the hybrid series of compounds. We are now focusing our efforts on identifying an inhibitor that is selective for the JMJD2 family over other JmjC domain-containing proteins.

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Qian, Shengzhan, Yingxiang Wang, Hong Ma, and Liangsheng Zhang. "Expansion and Functional Divergence of Jumonji C-Containing Histone Demethylases: Significance of Duplications in Ancestral Angiosperms and Vertebrates." Plant Physiology 168, no. 4 (June 9, 2015): 1321–37. http://dx.doi.org/10.1104/pp.15.00520.

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XIONG, C. "SUN-210 THE HISTONE DEMETHYLASE JUMONJI DOMAIN-CONTAINING PROTEIN 3 ACTS AS AN EPIGENETIC SUPPRESSOR OF RENAL FIBROSIS." Kidney International Reports 4, no. 7 (July 2019): S247. http://dx.doi.org/10.1016/j.ekir.2019.05.613.

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Hamada, Shohei, Tae-Dong Kim, Takayoshi Suzuki, Yukihiro Itoh, Hiroki Tsumoto, Hidehiko Nakagawa, Ralf Janknecht, and Naoki Miyata. "Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain-containing histone lysine demethylase inhibitors." Bioorganic & Medicinal Chemistry Letters 19, no. 10 (May 2009): 2852–55. http://dx.doi.org/10.1016/j.bmcl.2009.03.098.

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Lee, Hong Gil, and Pil Joon Seo. "The Arabidopsis JMJ29 Protein Controls Circadian Oscillation through Diurnal Histone Demethylation at the CCA1 and PRR9 Loci." Genes 12, no. 4 (April 5, 2021): 529. http://dx.doi.org/10.3390/genes12040529.

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The circadian clock matches various biological processes to diurnal environmental cycles, such as light and temperature. Accumulating evidence shows that chromatin modification is crucial for robust circadian oscillation in plants, although chromatin modifiers involved in regulating core clock gene expression have been limitedly investigated. Here, we report that the Jumonji C domain-containing histone demethylase JMJ29, which belongs to the JHDM2/KDM3 group, shapes rhythmic changes in H3K4me3 histone marks at core clock loci in Arabidopsis. The evening-expressed JMJ29 protein interacts with the Evening Complex (EC) component EARLY FLOWERING 3 (ELF3). The EC recruits JMJ29 to the CCA1 and PRR9 promoters to catalyze the H3K4me3 demethylation at the cognate loci, maintaining a low-level expression during the evening time. Together, our findings demonstrate that interaction of circadian components with chromatin-related proteins underlies diurnal fluctuation of chromatin structures to maintain circadian waveforms in plants.

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Roatsch, Martin, Dina Robaa, Martin Pippel, Joanne E. Nettleship, Yamini Reddivari, Louise E. Bird, Inga Hoffmann, et al. "Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases." Future Medicinal Chemistry 8, no. 13 (September 2016): 1553–71. http://dx.doi.org/10.4155/fmc.15.188.

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Izaguirre-Carbonell, Jesus, Christiansen Luke, Robert Burns, Jesse Schmitz, Chenxuan Li, Rebekah Mokry, Theresa Bluemn, Yongwei Zheng, Demin Wang, and Nan Zhu. "Critical Role of Jumonji Domain of JMJD1C in AML Leukemogenesis." Blood 132, Supplement 1 (November 29, 2018): 2599. http://dx.doi.org/10.1182/blood-2018-99-110463.

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Abstract MLL-rearranged leukemias are found in 5-10% of adult leukemias and over 70% of infant leukemias and are associated with intermediate to poor prognosis. We have recently shown that JMJD1C, a Jumonji domain containing lysine demethylase (KDM), is important for leukemia stem cell (LSC) function in MLL-AF9 and HOXA9 leukemias but dispensable for normal hematopoietic stem cell function, therefore a potential therapeutic target for acute myeloid leukemia (AML). To determine which domains within JMJD1C are essential for its function in AML, we performed a CRISPR/Cas9 negative selection screen against its coding sequence using guide RNAs (gRNA) tiled at ~ 30bp intervals. Specifically, gRNAs were cloned into a lenti-viral vector with a TdTomato marker gene, transduced into a clonal Cas9 expressing mouse MLL-AF9 leukemia and percentage of gRNA positive cells was analyzed by flow cytometry in a time course. JMJD1C Jumonji and Zinc finger domain (ZFD) and surrounding regions exhibited the most depletion at day 14 compare to day 2, comparable or higher than that of the positive control. To investigate the effect of mutating Jumonji and ZFD on MLL-AF9 leukemogenesis, we subject gRNA transduced MLL-AF9 Cas9 cells to colony forming cell assay. Mutating Jumonji or ZFD impaired colonegenic potential of MLL-AF9 Cas9 cells as evident by a significant reduction in the number of colonies. The resulting colonies appeared smaller and diffused, indicative of cell differentiation. Consistently, we observed impaired proliferation, increased apoptosis and increased expression of the myeloid differentiation marker Mac1 upon mutating these domains. Moreover, mutating Jumonji and ZFD prolonged survival of recipient mice compare to control in transplantation experiment. Finally, we performed chromatin-immunoprecipitation followed by sequencing (ChIP-seq) on H3K27, K36 and K9 methylation in JMJD1C knockout versus floxed MLL-AF9 leukemia cells to identify histone marks that correlate with JMJD1C activity. We observed increased H3K36 trimethylation (me3) level on JMJD1C regulated genes loci in the knockout cells compare to controls. Similar increase was observed upon mutating Jumonji and ZFD using CRISPR/Cas9 in ChIP assay. Using Gene Set Enrichment Analysis (GSEA), we found enrichment of JMJD1C regulated genes in the knockout cells in H3K36me3 ChIP-seq data but not H3K27me3 or H3K9 methylation data. Together, these data suggest that Jumonji and ZFD of JMJD1C are most critical for its function in AML and that methylated H3K36 can be used as a marker for JMJD1C activity at gene loci. Next, we performed single cell RNA-seq to examine the transcriptome change upon mutating the catalytic Jumonji domain. Our analysis showed a hierarchy within control leukemia cells with one cluster bearing more LSC property than the other. Upon mutating Jumonji domain, leukemia cells are driven into differentiated states that bear either more granulocyte or monocyte gene signatures. Using MAST, a single cell transcriptome GSEA tool, we observed enrichment of KRAS signatures in Jumonji mutated cells. This observation in addition to the increased expression of the IL-3 receptor subunit genes Csf2ra/b led us to examine whether the IL-3 signaling pathway is affected in these cells. Western blotting of IL-3 down signaling molecules ERK1/2 and STAT5 showed elevated phosphorylation in Jumonji mutated cells compare to controls both at basal level and in response to IL-3 stimulation. Consistently with this finding, Jumonji mutated cells showed increased sensitivity to inhibitors against RAS (Tipifarnib), MEK (Selumetinib) and JAK (Tofacitinib and Ruxolitinib). Finally, by mining published shRNA and gRNA screen, we observed that mouse as well as human MLLr leukemia cell lines with activating RAS mutations showed decreased or diminished response to knockdown or mutation of JMJD1C suggesting that the presence of RAS mutations render them resistant to JMJD1C modulation. Overall, we show that enzymatic domain of JMJD1C, the Jumonji domain, mediates its function in AML leukemogenesis, therefore can be targeted for potential therapeutic intervention. In addition, we uncovered a novel interplay between JMJD1C and IL-3 signaling pathway. Disclosures No relevant conflicts of interest to declare.

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Guo, Xiaoqiang, Yanmin Zhang, Qiang Zhang, Pingping Fa, Yaoting Gui, Guoquan Gao, and Zhiming Cai. "The regulatory role of nickel on H3K27 demethylase JMJD3 in kidney cancer cells." Toxicology and Industrial Health 32, no. 7 (November 26, 2014): 1286–92. http://dx.doi.org/10.1177/0748233714552687.

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Nickel compounds are an important class of environmental pollutants and carcinogens. Chronic exposure to nickel compounds has been connected with increased risks of numerous cancers, including lung and kidney cancers. But the precise mechanism by which nickel compounds exert their carcinogenic properties is not completely understood. In this study, kidney cancer cells namely human embryonic kidney 293-containing SV40 large T-antigen (HEK293T) and 786-0 were incubated with various concentrations of nickel chloride for 24 h before analysing the expression of three histone H3K27 methylation-modifying enzymes and H3K27me3 using quantitative real-time polymerase chain reaction, Western blot and immunofluorescence analyses. Our results showed that incubation of nickel chloride upregulated the expression of H3K27me3 demethylase jumonji domain-containing protein 3 (JMJD3) in kidney cancer cells, which was accompanied by the reduction in the protein level of H3K27me3. Enhanced demethylation of H3K27me3 may represent a novel mechanism underlying the carcinogenicity of nickel compounds.

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Luo, XiaoLing, Di Yang, WeiJun Wu, Fen Long, ChenXi Xiao, Ming Qin, Betty YuenKwan Law, et al. "Critical role of histone demethylase Jumonji domain-containing protein 3 in the regulation of neointima formation following vascular injury." Cardiovascular Research 114, no. 14 (July 4, 2018): 1894–906. http://dx.doi.org/10.1093/cvr/cvy176.

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Kim, Ji-Hyun, Dae Young Jung, Hye-Ran Kim, and Myeong Ho Jung. "Histone H3K9 Demethylase JMJD2B Plays a Role in LXRα-Dependent Lipogenesis." International Journal of Molecular Sciences 21, no. 21 (November 5, 2020): 8313. http://dx.doi.org/10.3390/ijms21218313.

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Ligand-activated liver X receptor α (LXRα) upregulates the expression of hepatic lipogenic genes, which leads to triglyceride (TG) accumulation, resulting in nonalcoholic fatty liver disease (NAFLD). Thus, LXRα regulation may provide a novel therapeutic target against NAFLD. However, histone methylation-mediated epigenetic regulation involved in LXRα-dependent lipogenesis is poorly understood. In this study, we investigated the functional role of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in LXRα-dependent lipogenesis. JMJD2B expression level was upregulated in HepG2 cells treated with LXRα agonist T0901317 or palmitate and the liver of mice administered with T0901317 or fed a high-fat diet. Knockdown of JMJD2B using siRNA abrogated T0901317-induced LXRα-dependent lipogenic gene expression and lowered intracellular TG accumulation. Conversely, overexpression of JMJD2B in HepG2 cells upregulated the expression of LXRα-dependent lipogenic genes, in line with increased intracellular TG levels. JMJD2B overexpression or T0901317 treatment induced the recruitment of JMJD2B and LXRα to LXR response elements (LXRE) in the promoter region of LXRα-target gene and reduced the enrichment of H3K9me2 and H3K9me3 in the vicinity of the LXRE. Furthermore, JMJD2B enhanced T0901317 or LXRα-induced transcriptional activities of reporters containing LXRE. A co-immunoprecipitation assay revealed that JMJD2B interacted with activated LXRα. Moreover, overexpression of JMJD2B in mice resulted in upregulation of hepatic LXRα-dependent lipogenic genes, consistent with development of hepatic steatosis. Taken together, these results indicate that JMJD2B plays a role in LXRα-mediated lipogenesis via removing the repressive histone marks, H3K9me2 and H3K9me3, at LXRE, which might contribute to hepatic steatosis.

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Ning, Ke, Yangguang Shao, Yuxin He, Fei Wang, Xi Cui, Furong Liu, Danni Li, and Feng Li. "Histone demethylase Jumonji domain‐containing 1A inhibits proliferation and progression of gastric cancer by upregulating runt‐related transcription factor 3." Cancer Science 111, no. 10 (September 6, 2020): 3679–92. http://dx.doi.org/10.1111/cas.14594.

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Alahari, Sruthi, Martin Post, Alessandro Rolfo, Rosanna Weksberg, and Isabella Caniggia. "Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression in Preeclampsia." Journal of Clinical Endocrinology & Metabolism 103, no. 4 (January 24, 2018): 1545–57. http://dx.doi.org/10.1210/jc.2017-02197.

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Abstract Context The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5% to 7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive. Objective We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia. Design, Setting, and Participants Placentae were obtained from early-onset preeclampsia (n = 56; <34 weeks of gestation) and late-onset preeclampsia (n = 19; ≥34 weeks of gestation). Placentae from healthy normotensive age-matched preterm control (n = 43) and term control (n = 23) pregnancies were included as controls. Main Outcome Measure(s) We measured the activity of Jumonji domain containing protein 6 (JMJD6), a ferrous iron (Fe2+)– and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL. Results JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592–treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592–treated mice. Conclusions Our study uncovers epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia.

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Cellot, Sonia, Kristin J. Hope, Martin Sauvageau, Jalila Chagraoui, Eric Deneault, Tara MacRae, Nadine Mayotte, and Guy Sauvageau. "A Functional In Vivo RNAi screen Involving Jumonji C Domain Containing Candidates Unravels Kdm5b As a Negative Modulator of Hematopoietic Stem Cell Self-Renewal." Blood 118, no. 21 (November 18, 2011): 385. http://dx.doi.org/10.1182/blood.v118.21.385.385.

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Abstract Abstract 385 Epigenetic modifications influence chromatin accessibility, impacting on cell fate decisions, such as stem cell self-renewal and differentiation, in both normal and leukemic stem cells (LSC). To investigate the putative role of histone demethylases (HDM) in modulating primary hematopoietic stem cell (HSC) fate, an in vivo functional screen was performed, using an RNAi based strategy, involving 25 members of the Jumonji (JmjC) domain protein family. As a first step, expression profile studies of these gene candidates were undertaken. Transcripts of all these enzymes were detected in isolated HSC populations (frequency 1:2) from fetal liver (n=1) and bone marrow (n=2), except for Hairless. As compared to unsorted bone marrow (BM), stem cells harboured higher expression of Jarid1b (relative-fold enrichment (RQ) of 3.9±1.7), Jmjd2d (RQ3.8±1.9), and Jhdm1b (3.1±1.7). Next, 5shRNA were designed against each of the 25 JmjC containing proteins, and cloned into a retroviral LMP vector encoding GFP to permit tracking of transduced cells in vivo. HSC-enriched CD150+CD48−Lin−cells (∼60 LT-HSC) were infected over 5 days by co-culture with retroviral producer cells in an arrayed 96-well format, with one shRNA per well. Directly after infection, the in vivo reconstituting potential of ¼ of each well was evaluated through duplicate competitive repopulation assays involving the co-transplantation of 1.5 × 105 congenic BM competitor cells into irradiated recipients. The remaining cell fraction served to asses gene transfer by GFP epifluorescence measurements, and RNA isolated from sorted GFP+ cells was used to evaluate gene knockdown levels by Q-RT-PCR analysis. Blood reconstitution was evaluated at an early (4wks) and late time point (16–20wks), tracking the contribution of the donor CD45.1+ transduced (GFP+) cells to recipient hematopoiesis over time. As baseline references, sh-RNA to Luciferase (no effect) and the histone acetyl transferase Myst3 (stem cell loss) were used, as well as Hoxb4 over-expression (stem cell expansion). The primary screen, followed by validation experiments, unravelled one positive (Jhdm1f/Phf8) and two negative (Jarid1b, Hif1an) regulators of HSC activity. The strongest impact was seen with Jarid1b knockdown, and the resulting gain in HSC activity. As a confirmation step, cells were kept in culture for one week, to better contrast an increase in HSC activity, compared to control HSC. After 7 days in vitro, 1/8 equivalents of single well cultures were transplanted into 3 mice, and blood reconstitution levels serially assessed. Cells transduced with sh-RNA against Jarid1b contributed more significantly to host hematopoiesis than sh-RNA Luciferase transduced cells (58±16% vs 26±3% GFP), or Hoxb4 over-expressing cells (37±2% GFP), at comparable gene transfer rates, at the 16 week time point and beyond (3 independent experiments). Long-term HSC frequencies were evaluated from these cultures, and found to be 6–10 fold increased in shJari1d1b-cell cultures. In long-term recipients, differentiation potential of these cells was preserved, as evidenced by CD4+CD8+ thymic cells, B220+ splenic cells and CD11b+ bone marrow cells in the GFP positive contingent. Clonality studies on DNA isolated from these sorted populations confirmed oligoclonality of the stem cell expansion, and HSC pluripotency. There were no cases of leukemic transformation in all of the transplant recipients (n>30). As assessed by Q-RT-PCR, levels of HoxA5, HoxA9, HoxA10 and CxCl5 were increased in day7 sh3Jarib1b-cells (vs ctl), while the levels of the tumor suppressors Cav1, Sash1 and Egr1 were decreased. A more detailed assessment of the HoxA cluster revealed predominant expression of 5' cluster genes in expanding shJarib1b-cells, from HoxA5 to HoxA11, with a concomitant increase in the level of H3K4 tri-methylation, as assessed by ChIP-CHIP. In conclusion, HDM of the JmjC family can modulate HSC activity, both positively and negatively. These data suggest that the H3K4 demethylase Jarid1b (KDM5b) restrains stem cell self-renewal, acting as a co-repressor, possibly via epigenetic regulation of the HoxA gene cluster, among other target genes. This observation could be further exploited as an HSC expansion strategy. Disclosures: No relevant conflicts of interest to declare.

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Dupere-Richer, Daphne, Jianping Li, Sayantan Maji, Crissandra Pipe, Sharon Norton, Teresa Ezponda, Richard Lynn Bennett, and Jonathan D. Licht. "Loss of KDM6A/UTX Accelerate the Development of Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 1004. http://dx.doi.org/10.1182/blood-2018-99-113835.

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Abstract In multiple myeloma (MM), inactivating mutations and deletions affecting the histone demethylase KDM6A locus are found in up to 10% of newly diagnosed patients and associated with poor prognosis. KDM6A (also named UTX, Ubiquitously transcribed Tetratricopeptide repeat, X chromosome) belongs to a family of Jumonji-C (Jmj-C)-containing demethylases that work as a scaffold for a multiprotein complex containing H3K4 specific methyltransferases KMT2D and/or KMT2C (MLL2/3), the histone acetyltransferase CBP/p300 and members of the SWI/SNF chromatin-remodeling complex. In a concerted manner this complex appears to add activation marks on histones and remove methylation of lysine 27 on histone H3 (H3K27me) associated with gene repression. Importantly, all these coregulators are found significantly mutated in MM and their function may converge into a tumor suppressive pathway. Our goal is to understand how KDM6A loss contributes to the development of MM. We modeled the loss of KDM6A in MM cell lines using CRISPR-Cas9 ribonucleotide protein (RNP) technology. Mutant allele frequency over time post electroporation of RNP revealed a growth advantage of KDM6A mutant alleles. By 2 weeks of growth most of the cells in culture harbored KDM6A gene disruption and exhibit elimination of KDM6A protein confirming the tumor suppressive role of KDM6A in MM. We used these isogenic polyclonal edited cell lines with KDM6A wild type or mutated to identify KDM6A binding sites and enhancers affected by the loss of KDM6A. As well, we knock-in an HA tag on endogenous KDM6A to identify DNA regions occupied by KDM6A. To understand the importance of KDM6A demethylase activity in the tumor suppressive effect of KDM6A, we developed stable cell lines with a doxycycline-inducible form of KDM6A wild-type (WT) or lacking demethylase activity (JmjC-dead). We found that about 20% of the genes deregulated by re-expression of WT and jmjC-dead KDM6A overlap suggesting that demethylase activity is not essential for all KDM6A functions in MM. Importantly, we confirmed the tumor suppressive role of KDM6A in a novel mouse model of MM in which KDM6A is deleted specifically in the B cell compartment. Briefly, we isolated CD19cre-/+ (control) or CD19cre-/+ Kdm6afl/fl fetal liver cells and transduced these cells with a constitutively activated form of the IL-6 coreceptor (L-GP130) that activates the JAK/STAT pathway. Mice transplanted with CD19cre-/+ Kdm6afl/fl fetal liver cells developed MM by 7 weeks post transplantation while mice transplanted with CD19cre+/- fetal liver cells did not developed MM by20 weeks. Necroscopy and flow cytometry analysis demonstrated infiltration of CD138+ cells in bone marrow, spleen, liver and kidney of mice that developed MM. In the future we will use this model to explore how loss of KDM6A affects chromatin structure in vivo and how it changes the characteristics of MM. These studies are expected to provide new insights that lead to the development of more effective MM therapies which directly target mechanisms of chromatin structure regulation. Disclosures Licht: Celgene: Research Funding.

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Perrigue, Patrick M., Magdalena Rakoczy, Kamila P. Pawlicka, Agnieszka Belter, Małgorzata Giel-Pietraszuk, Mirosława Naskręt-Barciszewska, Jan Barciszewski, and Marek Figlerowicz. "Cancer Stem Cell-Inducing Media Activates Senescence Reprogramming in Fibroblasts." Cancers 12, no. 7 (June 30, 2020): 1745. http://dx.doi.org/10.3390/cancers12071745.

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Cellular senescence is a tumor-suppressive mechanism blocking cell proliferation in response to stress. However, recent evidence suggests that senescent tumor cells can re-enter the cell cycle to become cancer stem cells, leading to relapse after cancer chemotherapy treatment. Understanding how the senescence reprogramming process is a precursor to cancer stem cell formation is of great medical importance. To study the interplay between senescence, stemness, and cancer, we applied a stem cell medium (SCM) to human embryonic fibroblasts (MRC5 and WI-38) and cancer cell lines (A549 and 293T). MRC5 and WI-38 cells treated with SCM showed symptoms of oxidative stress and became senescent. Transcriptome analysis over a time course of SCM-induced senescence, revealed a developmental process overlapping with the upregulation of genes for growth arrest and the senescence-associated secretory phenotype (SASP). We demonstrate that histone demethylases jumonji domain-containing protein D3 (Jmjd3) and ubiquitously transcribed tetratricopeptide repeat, X chromosome (Utx), which operate by remodeling chromatin structure, are implicated in the senescence reprogramming process to block stem cell formation in fibroblasts. In contrast, A549 and 293T cells cultured in SCM were converted to cancer stem cells that displayed the phenotype of senescence uncoupled from growth arrest. The direct overexpression of DNA methyltransferases (Dnmt1 and Dnmt3A), ten-eleven translocation methylcytosine dioxygenases (Tet1 and Tet3), Jmjd3, and Utx proteins could activate senescence-associated beta-galactosidase (SA-β-gal) activity in 293T cells, suggesting that epigenetic alteration and chromatin remodeling factors trigger the senescence response. Overall, our study suggests that chromatin machinery controlling senescence reprogramming is significant in cancer stem cell formation.

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Roy, Sambit, Binbin Huang, Niharika Sinha, Jianrong Wang, and Aritro Sen. "Androgens regulate ovarian gene expression by balancing Ezh2-Jmjd3 mediated H3K27me3 dynamics." PLOS Genetics 17, no. 3 (March 30, 2021): e1009483. http://dx.doi.org/10.1371/journal.pgen.1009483.

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Conventionally viewed as male hormone, androgens play a critical role in female fertility. Although androgen receptors (AR) are transcription factors, to date very few direct transcriptional targets of ARs have been identified in the ovary. Using mouse models, this study provides three critical insights about androgen-induced gene regulation in the ovary and its impact on female fertility. First, RNA-sequencing reveals a number of genes and biological processes that were previously not known to be directly regulated by androgens in the ovary. Second, androgens can also influence gene expression by decreasing the tri-methyl mark on lysine 27 of histone3 (H3K27me3), a gene silencing epigenetic mark. ChIP-seq analyses highlight that androgen-induced modulation of H3K27me3 mark within gene bodies, promoters or distal enhancers have a much broader impact on ovarian function than the direct genomic effects of androgens. Third, androgen-induced decrease of H3K27me3 is mediated through (a) inhibiting the expression and activity of Enhancer of Zeste Homologue 2 (EZH2), a histone methyltransferase that promotes tri-methylation of K27 and (b) by inducing the expression of a histone demethylase called Jumonji domain containing protein-3 (JMJD3/KDM6B), responsible for removing the H3K27me3 mark. Androgens through the PI3K/Akt pathway, in a transcription-independent fashion, increase hypoxia-inducible factor 1 alpha (HIF1α) protein levels, which in turn induce JMJD3 expression. Furthermore, proof of concept studies involving in vivo knockdown of Ar in the ovary and ovarian (granulosa) cell-specific Ar knockout mouse model show that ARs regulate the expression of key ovarian genes through modulation of H3K27me3.

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Choi, I., and K. H. S. Campbell. "24 EFFECTS OF HISTONE METHYLATION RELATED GENES ON EPIGENETIC REPROGRAMMING AND ZYGOTIC GENE ACTIVATION IN OVINE SOMATIC CELL NUCLEAR TRANSFER (SCNT) EMBRYOS." Reproduction, Fertility and Development 21, no. 1 (2009): 112. http://dx.doi.org/10.1071/rdv21n1ab24.

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After fertilization, early embryo development is dependent upon maternally inherited proteins and protein synthesised from maternal mRNA until zygotic gene activation (ZGA) occurs. The transition of transcriptional activity from maternal to embryonic control occurs with the activation of rRNA genes and the formation of the nucleolus at the 8- to 16-cell stage that coincides with a prolonged fourth cell cycle in bovine and ovine embryos. However, previous studies have reported a shift in the longest cell cycle (fifth cell cycle) in bovine somatic cell nuclear transfer (SCNT) embryos, suggesting that the major genome activation is delayed, possibly due to incomplete changes in chromatin structure such as hypermethylation and hypoacetylation of histone (Memili and First 2000 Zygote 8, 87–96; Holm et al. 2003 Cloning Stem Cells 5, 133–142). Although global gene expression profile studies have been carried out in somatic cell nuclear transfer embryos, little is known about the expression of genes which can alter chromatin structure in early embryo development and possibly effect ZGA. To determine whether epigenetic reprogramming of donor nuclei affected ZGA and expression profiles in SCNT embryos, ZBTB33 (zinc finger and BTB domain containing 33, also known as kaiso, a methy-CpG specific repressor), BRG1(brahma-related gene 1, SWI/SNF family of the ATP-dependent chromatin remodeling complexes), JMJD1A (jumonji domain containing 1A, H3K9me2/1-specific demethylase), JMJD1C (putative H3K9-specific demethylase), and JMJD2C (H3K9me3-specific demethylase) were examined by RT-PCR at different developmental stages [germinal vesicle (GV), metaphase II (MII), 8- to 16-cell, 16- to 32-cell, and blastocyst in both parthenogenetic and SCNT embryos]. All genes were detected in parthenogenetic and SCNT blastocyts, and ZBTB33 was also expressed in all embryos at all stages tested. However, the onset of expression of JMJD1C, containing POU5F1 binding site at 5′-promoter region and BRG1 required for ZGA are delayed in SCNT embryos as compared to parthenotes (16- v. 8-cell, and blastoocyst v. 16-cell stage). Furthermore, JMJD2C containing NANOG binding sites at the 3′-flanking region was expressed in GV and MII oocytes and parthenogenetic blastocysts, whereas in SCNT embryos, JMJD2C was only observed from the 16-cell stage onwards. Interestingly, JMJD1A, which is positively regulated by POU5F1, was not detected in GV and MII oocytes but was present in blastocyst stage embryos of both groups. Taken together, these results suggest that incomplete epigenetic modifications of genomic DNA and histones lead to a delayed onset of ZGA which may affect further development and establishment of totipotency. Subsequently, aberrant expression patterns reported previously in SCNT embryos may be attributed to improper expression of histone H3K9 and H3K4 demethylase genes during early embryo development.

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Fan, Lingling, Fengbo Zhang, Songhui Xu, Xiaolu Cui, Arif Hussain, Ladan Fazli, Martin Gleave, Xuesen Dong, and Jianfei Qi. "Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells." Proceedings of the National Academy of Sciences 115, no. 20 (April 30, 2018): E4584—E4593. http://dx.doi.org/10.1073/pnas.1802415115.

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Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

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Liang, Chung-Yi, Long-Chi Wang, and Wan-Sheng Lo. "Dissociation of the H3K36 demethylase Rph1 from chromatin mediates derepression of environmental stress-response genes under genotoxic stress in Saccharomyces cerevisiae." Molecular Biology of the Cell 24, no. 20 (October 15, 2013): 3251–62. http://dx.doi.org/10.1091/mbc.e12-11-0820.

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Cells respond to environmental signals by altering gene expression through transcription factors. Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C2H2 zinc-finger protein family. Here we investigate the regulatory network of Rph1 in yeast by expression microarray analysis. More than 75% of Rph1-regulated genes showed increased expression in the rph1-deletion mutant, suggesting that Rph1 is mainly a transcriptional repressor. The binding motif 5′-CCCCTWA-3′, which resembles the stress response element, is overrepresented in the promoters of Rph1-repressed genes. A significant proportion of Rph1-regulated genes respond to DNA damage and environmental stress. Rph1 is a labile protein, and Rad53 negatively modulates Rph1 protein level. We find that the JmjN domain is important in maintaining protein stability and the repressive effect of Rph1. Rph1 is directly associated with the promoter region of targeted genes and dissociated from chromatin before transcriptional derepression on DNA damage and oxidative stress. Of interest, the master stress-activated regulator Msn2 also regulates a subset of Rph1-repressed genes under oxidative stress. Our findings confirm the regulatory role of Rph1 as a transcriptional repressor and reveal that Rph1 might be a regulatory node connecting different signaling pathways responding to environmental stresses.

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Ishii, Makoto, Haitao Wen, Callie A. S. Corsa, Tianju Liu, Ana L. Coelho, Ronald M. Allen, William F. Carson, et al. "Epigenetic regulation of the alternatively activated macrophage phenotype." Blood 114, no. 15 (October 8, 2009): 3244–54. http://dx.doi.org/10.1182/blood-2009-04-217620.

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Abstract Alternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing 3 (Jmjd3). We found that continuous interleukin-4 (IL-4) treatment leads to decreased H3K27 methylation, at the promoter of M2 marker genes, and a concomitant increase in Jmjd3 expression. Furthermore, we demonstrate that IL-4–dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4–mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. Increased Jmjd3 contributes to the decrease of H3K27 dimethylation and trimethylation (H3K27me2/3) marks as well as the transcriptional activation of specific M2 marker genes. The decrease in H3K27me2/3 and increase in Jmjd3 recruitment were confirmed by in vivo studies using a Schistosoma mansoni egg–challenged mouse model, a well-studied system known to support an M2 phenotype. Collectively, these data indicate that chromatin remodeling is mechanistically important in the acquisition of the M2-macrophage phenotype.

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Hamada, Shohei, Takayoshi Suzuki, Koshiki Mino, Koichi Koseki, Felix Oehme, Ingo Flamme, Hiroki Ozasa, et al. "Design, Synthesis, Enzyme-Inhibitory Activity, and Effect on Human Cancer Cells of a Novel Series of Jumonji Domain-Containing Protein 2 Histone Demethylase Inhibitors." Journal of Medicinal Chemistry 53, no. 15 (August 12, 2010): 5629–38. http://dx.doi.org/10.1021/jm1003655.

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Rohatgi, Nidhi, Wei Zou, Patrick L. Collins, Jonathan R. Brestoff, Timothy H. Chen, Yousef Abu-Amer, and Steven L. Teitelbaum. "ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1." Blood Advances 2, no. 19 (September 28, 2018): 2467–77. http://dx.doi.org/10.1182/bloodadvances.2018018309.

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Abstract Additional sex comb-like 1 (ASXL1) mutations are commonly associated with myeloid malignancies and are markers of aggressive disease. The fact that ASXL1 is necessary for myeloid differentiation raises the possibility it also regulates osteoclasts. We find deletion of ASXL1 in myeloid cells results in bone loss with increased abundance of osteoclasts. Because ASXL1 is an enhancer of trithorax and polycomb (ETP) protein, we asked if it modulates osteoclast differentiation by maintaining balance between positive and negative epigenetic regulators. In fact, loss of ASXL1 induces concordant loss of inhibitory H3K27me3 with gain of H3K4me3 at key osteoclast differentiation genes, including nuclear factor for activated T cells 1 (NFATc1) and itgb3. In the setting of ASXL1 deficiency, increased NFATc1 binds to the Blimp1 (Prdm1) promoter thereby enhancing expression of this pro-osteoclastogenic gene. The global reduction of K27 trimethylation in ASXL1-deficient osteoclasts is also attended by a 40-fold increase in expression of the histone demethylase Jumonji domain-containing 3 (Jmjd3). Jmjd3 knockdown in ASXL1-deficient osteoclast precursors increases H3K27me3 on the NFATc1 promoter and impairs osteoclast formation. Thus, in addition to promoting myeloid malignancies, ASXL1 controls epigenetic reprogramming of osteoclasts to regulate bone resorption and mass.

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Alves, Juliano, Gediminas Vidugiris, Said A. Goueli, and Hicham Zegzouti. "Bioluminescent High-Throughput Succinate Detection Method for Monitoring the Activity of JMJC Histone Demethylases and Fe(II)/2-Oxoglutarate-Dependent Dioxygenases." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 3 (December 14, 2017): 242–54. http://dx.doi.org/10.1177/2472555217745657.

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The modification of a diverse array of substrates by Fe(II)/2-oxoglutarate-dependent dioxygenases is central to the modulation of distinct biological processes such as epigenetics, hypoxic signaling, and DNA/RNA repair. Of these, JumonjiC domain–containing histone lysine demethylases (JMJCs) and prolyl hydroxylases are potential drug targets due to their relevance to human diseases. Thus, assays to interrogate this enzyme superfamily are needed to identify selective and potent inhibitors as leads for drug development and that could also be useful research tools. Since succinate is a common product to all Fe(II)/2-oxoglutarate-dependent dioxygenase reactions, a method that detects succinate would be suitable to all members of this enzyme superfamily. We therefore developed a bioluminescent and homogenous succinate detection assay and validated its use with diverse sets of enzyme classes. We evaluated the substrate specificities of these enzymes, their apparent kinetic constants, and inhibition profiles and mode of action of reported and novel inhibitors. Our results indicate that succinate detection is a useful readout for the monitoring of enzymatic activities with distinct substrate entities, as well as for the discovery of novel inhibitors. By investigating a large number of Fe(II)/2-oxoglutarate-dependent enzymes, this method could have a significant impact on the field of dioxygenase research.

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Journal articles on the topic 'Jumonji Domain-Containing Histone Demethylases'

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