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Littérature scientifique sur le sujet « HDAC 3 »

Auteur : Grafiati

Publié le 26 octobre 2023

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Articles de revues sur le sujet "HDAC 3"

Bertos, Nicholas R., Audrey H. Wang et Xiang-Jiao Yang. « Class II histone deacetylases : Structure, function, and regulation ». Biochemistry and Cell Biology 79, n^o 3 (1 juin 2001) : 243–52. http://dx.doi.org/10.1139/o01-032.

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Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hda1. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.Key words: histone acetylation, protein acetylation, histone deacetylase, 14-3-3 proteins.

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Ozawa, Yukiyasu, Masayuki Towatari, Shinobu Tsuzuki, Fumihiko Hayakawa, Takahiro Maeda, Yasuhiko Miyata, Mitsune Tanimoto et Hidehiko Saito. « Histone deacetylase 3 associates with and represses the transcription factor GATA-2 ». Blood 98, n^o 7 (1 octobre 2001) : 2116–23. http://dx.doi.org/10.1182/blood.v98.7.2116.

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The zinc finger transcription factor GATA-2 plays a critical role in the survival and proliferation of hematopoietic stem cells. This study examined the interaction of GATA-2 with histone deacetylases (HDACs) to define the involvement of HDACs in the regulation of GATA-2 function. GATA-2 directly associates with HDAC3 but not with HDAC1. Consistent with this, HDAC3 suppressed the transcriptional potential of GATA-2, whereas HDAC1 did not affect GATA-2–dependent transcription. Results further demonstrated that GATA-2 and HDAC3 colocalized in the nucleus. These results identify GATA-2 as a nuclear target for HDAC3-mediated repression. Furthermore, GATA-2 also directly associated with HDAC5 but not with other class II HDACs examined, that is, HDAC4 and HDAC6. This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members.

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Stubbs, Matthew C., Won-Il Kim, Tina Davis, Jun Qi, James Bradner, Andrew L. Kung et Scott A. Armstrong. « Selective Inhibition of HDAC1 and HDAC2 Is a Potential Therapeutic Option for B-All ». Blood 116, n^o 21 (19 novembre 2010) : 2900. http://dx.doi.org/10.1182/blood.v116.21.2900.2900.

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Abstract Abstract 2900 Histone deacetylase inhibitors (HDACi) have emerged as potent anticancer agents, and could open the door for future epigenetic therapies. As our understanding of the importance of epigenetic histone modifications in B-cell acute lymphoblastic leukemia (B-ALL) increases, we hypothesized that HDACi could potentially be a useful therapeutic option. The pan-HDAC inhibitor LAQ824 (Novartis) was toxic to B-ALLs in low nM concentrations in vitro, and treated cells had increased p21 and DNA damage response as indicated by increased γH2A.X protein levels. Additionally, the related compound panobinostat (Novartis) reduced leukemic burden from B-ALL patient samples in primary xenograft models, indicating that pan-HDAC inhibition is a putative B-ALL therapeutic option. To determine HDAC isoform-specific effects, we used a high throughput assay that exposed B-ALL cell lines to a panel of HDAC inhibitors. This screen indicated that tubacin, an HDAC6 specific inhibitor, cannot inhibit B-ALL cell growth within a dose range where HDAC6 is the only HDAC targeted. This finding was further validated using another HDAC6 specific inhibitor, WT-161. The screen also indicated that benzimide compounds such as MGCD-0103 (MethylGene) and MS-275 (Entinostat, Syndax) which only target class I HDACs (HDAC1-3) effectively inhibited growth in the cell lines. These data indicate that inhibiting the class I HDACs is sufficient to suppress B-ALL cell line growth. To determine which HDACs are necessary for cell viability, we lentivirally introduced isoform-specific shRNAs into our ALL cell lines. Knockdown of HDAC1 or HDAC2 resulted in p21 induction, slowed growth rate and resulted in a modest increase in apoptosis. Knockdown of HDAC3 lead to increased p21 and γH2A.X protein levels, along with induction of apoptosis, closely mimicking the results of pan-HDAC inhibitor treatment of the cells. Although depletion of HDAC3 had a more immediate impact on B-ALL viability by comparison to HDAC1/2, concerns about the contribution of HDAC3 inhibition to toxicity led us to further investigate whether specific inhibition of HDAC1/2 might be efficacious in B-ALL. Treatment of B-ALL cells with Merck 60, a tool compound with selectivity for HDAC1/2, was efficacious against was effective against B-ALL lines in the low to mid nM range. The kinetics of growth suppression were slower with this compound than with the pan-HDAC inhibitors. Using this compound, the ALL lines required 72 hours of exposure before cell growth was diminished, and apoptosis ensued. This may be due to the increased time necessary to accumulate acetylated histone marks as observable by western blot (18 hours for Merck 60 vs. 2–4 hours for LAQ824). Increased levels of p21 and γH2A.X were also observed. Interestingly, AML cell lines were much less sensitive to the HDAC1/2 specific inhibitor than were the B-ALL lines (roughly 5–10 fold), whereas pan-HDAC inhibitors were equally effective against AML and ALL. Additionally, non-hematopoietic tumor derived cell lines were insensitive to Merck 60, with EC50 values exceeding 20μM. Our findings indicate that pan-HDAC and class I specific HDAC inhibitors are possible therapeutic options for B-ALL. In contrast to most other cancer cell types studied, selective inhibition of HDAC1 and HDAC2 was sufficient to induce apoptosis in B-ALL lines. Together, these results suggest that small molecules specifically targeting HDAC1/2 may have therapeutic utility in B-ALL, and may provide improved therapeutic index by comparison to pan-HDAC or class I HDAC inhibitors that also target HDAC3. Disclosures: No relevant conflicts of interest to declare.

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Varricchio, Lilian, Carmela Dell'Aversana, Angela Nebbioso, Giovanni Migliaccio, Lucia Altucci, James J. Bieker et Anna Rita F. Migliaccio. « Identification of a New Functional HDAC Complex Composed by HDAC5, GATA1 and EKLF in Human Erythroid Cells ». Blood 120, n^o 21 (16 novembre 2012) : 979. http://dx.doi.org/10.1182/blood.v120.21.979.979.

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Abstract Abstract 979 Histone deacetylation, the reaction that maintains chromatin in a condensed configuration preventing gene expression, is catalyzed by the histone deacetylase (HDAC) superfamily. The human HDAC family includes 18 different isoforms classified on the basis of their sequence homology to HDACs from Saccharomyces Cerevisiae into class I (HDAC1, −2, −3, and −8), IIa (HDAC4, −5, −7, and −9), IIb (HDAC6 and −10) and IV (HDAC11). Class I HDACs bind the DNA directly while class IIa HDACs shuffles other proteins between nucleus and cytoplasm. While the role of individual class I HDACs in erythropoiesis is starting to emerge, that of class IIa and b HDACs is still largely unknown. To clarify the role played by class IIa HDACs in the control of human erythropoiesis, an extensive analysis of expression, activity, and function of different classes of HDACs during the maturation of erythroblasts derived in vitro from adult blood or cord blood was performed. HDACs expression/activity. Erythroid maturation was associated with increased expression of class I HDACs (both mRNA and protein) which, in the case of HDAC1, was also associated with increased enzymatic activity and association with its NuRD partner GATA1. By contrast, reductions either in expression (HDAC4) or activity (HDAC5) of class IIa HDACs were observed with maturation. In addition, GATA1 and EKLF were consistently found associated in human erythroblasts but EKLF was not found associated with HDAC1. The extent of nuclear-cytoplasmic trafficking of class I (HDAC1 and 2) and IIa (HDAC4 and 5) and of the transcription factors EKLF and GATA1 in response to EPO was determined. HDAC2/EKLF/GATA1 and HDAC4 were found constitutively present in the nucleus and in the cytoplasm, respectively. By contrast, the nuclear concentration of HDAC1 increased while that of HDAC5 and of GATA1fl decreased upon stimulation with EPO. The last two observations suggested that HDAC5, GATA1 and EKLF might be associated in a complex. Identification of the HDAC5/EKLF/GATA1 complex. A series of IPs followed by WB experiments showed that HDAC5 was consistently associated with EKLF and GATA1 and conversely, both GATA1 (preferentially GATA1fl over GATA1s) and EKLF were consistently associated with HDAC5 (Fig 1A and not shown). Interestingly also pERK was detected in IPs with HDAC5, EKLF and GATA1 antibodies. These results indicate that in erythroid cells HDAC5 forms a complex with GATA1, EKLF and pERK. Identification of the biological activity of the HDAC5/GATA1/EKLF/pERK complex. The association between GATA1/EKLF was greater in cells generated with cord blood (which express high HbF levels) than in those derived from adult blood and their association decreased with maturation, suggesting that the complex may regulate HbF expression. To confirm this hypothesis, HDAC5/GATA1 association and γ/(γ+ β) mRNA ratios were determined in erythroid cells induced to mature in the presence of a pan-class II-specific (APHA9, ID50=20 μM for HDAC4) HDAC inhibitor (HDACi) (Fig 1B)1. Cells exposed in parallel to the class I/IIa-specific (UBHA24, ID50 =0.2 and 0.6 μM for HDAC1 and HDAC4, respectively) HDACi, were used as control. Exposure to APHA9 reduced the association between GATA1 and HDAC5 and increased γ/(γ + β) mRNA expression ratio, while this association was not affected by exposure to the class I/II HDACi which, as expected, also increased γ/(γ+ β) mRNA ratio. Conclusions. These data identify a new HDAC complex formed by HDAC5, EKLF and GATA1 that regulates γ/(γ + β) ratio. We hypothesize that the biological role of this new complex is to shuffle GATA1 and EKLF from the cytoplasm to the nucleus, making them able to engage into the NuRD and Sin3A complex respectively, and that inhibition of the activity of this complex affects γ-globin expression indirectly by limiting the amount of GATA1and EKLF available to associate with NuRD and Sin3A. Disclosures: No relevant conflicts of interest to declare.

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Migliaccio, Giovanni, Carmela Dell’Aversana, Angela Nebbioso, Elena Alfani, Lilian arricchio, Antonello Mai, Pratima Chaurasia et al. « Ontogenic-Specific Increasesin HDAC1 Activity and Transcription Factor Association During the Maturation of Human Adult Erythroblasts in Vitro. » Blood 114, n^o 22 (1 novembre 2009) : 1978. http://dx.doi.org/10.1182/blood.v114.22.1978.1978.

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Abstract Abstract 1978 Poster Board I-1000 Histone deacetylation is one of the major pathways that maintains chromatin in a condensed configuration preventing gene expression in eukaryotic cells. The deacetylation reaction is catalyzed by the histone deacetylase (HDAC) superfamily, which includes eighteen distinct enzymes. HDACs perform their biological function as multiprotein complexes (Sin3A, NuRD and CoREST) that include at least two HDAC isoforms, DNA docking factors (transcription factors and methyl-binding proteins) and protein kinases (PKC). Data from murine cell lines suggest that association of HDAC1 with EKLF and/or Gata1, which occurs as part of the Sin3A or NuRD complex, may provide specificity to the regulation exerted by this enzyme during erythroid maturation. The role of HDAC complexes in primary human erythroid cells has remained poorly defined. The objective of this study was to characterize HDAC expression in human erythroblasts (EB) and monitor changes in expression and activity during maturation in response to erythropoietin (EPO). Human immature EB (iEB) were generated by culturing adult blood (AB) and cord blood (CB) mononuclear cells for 10-12 days with SCF, IL-3, EPO, dexamethasone and estradiol and then for 24-72 hrs in cultures containing EPO alone (mature EB, mEB) (Migliaccio et al, BCMC 28:168, 2002). The levels of HDAC isoform mRNAs and proteins expressed by iEB and mEB, as well as levels of HDAC1 and HDAC5 activity and association of HDAC1 with either GATA1 or EKLF, were then determined. By quantitative RT-PCR, iEB expressed detectable levels of mRNA for all HDAC isoforms, including SIRT 1 and 2. Induction of maturation had modest effects on the level of HDAC mRNA expressed by the EB with the exception of the mRNA for SIRT2 (increased by 10-fold), HDAC2 and HDAC6 (both increased by 2-3-fold). The increase in HDAC6 mRNA observed with maturation correlated with that of GATA1 (HDAC6 is immediately downstream to GATA1). By western-blot analyses, iEB expressed high levels only of HDAC1 to 5 and SIRT1 and 2. Induction of maturation did not affect the HDAC2 and HDAC3 but decreased HDAC1, HDAC4 and HDAC5 and increased SIRT2 protein levels. Therefore, the levels of mRNAs for these genes remained constant but their protein levels decreased with maturation. To evaluate the effect of decrements in protein level on enzymatic activity, the activity of complexes immunoprecipitated with antibodies specific for HDAC1 and HDAC5, the enzymes whose content decreased the most with maturation, from similar numbers of iEB and mEB was compared. iEB expressed HDAC1 and HDAC5 activity levels 2-fold greater than the standard (HeLa extracts). In agreement with the protein levels, HDAC5 activity decreased (by 1-log) with maturation. However, the activity of HDAC1 increased by 2-fold upon EPO exposure. To further characterize the interactions between transcription factors with HDAC1 within the complex, western-blot analyses of proteins co-immunoprecipitated with GATA1 (or HDAC1) from iEB and mEB obtained from CB and AB were compared (see Figure). A greater fraction of GATA 1 was associated with HDAC1 and EKLF in iEB obtained from CB than in those obtained from AB and in both cases the association increased with maturation. In conclusion, these results extend those previously observed with cell lines (Chen and Bieker, Mol Cell Biol 24:10416, 2004) and suggest that erythroid maturation of primary cells is associated with the dynamic regulation of the HDAC1-complex that includes increased enzymatic activity and ontogenetic-specific re-organization of transcription factors recruited to the complex. Disclosures: No relevant conflicts of interest to declare.Disclosures: No relevant conflicts of interest to declare.

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Hess, Lena, Verena Moos, Arnel A. Lauber, Wolfgang Reiter, Michael Schuster, Natascha Hartl, Daniel Lackner et al. « A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation ». PLOS Genetics 18, n^o 8 (22 août 2022) : e1010376. http://dx.doi.org/10.1371/journal.pgen.1010376.

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The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimicks class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.

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Keedy, Kara S., Nancie M. Archin, Adam T. Gates, Amy Espeseth, Daria J. Hazuda et David M. Margolis. « A Limited Group of Class I Histone Deacetylases Acts To Repress Human Immunodeficiency Virus Type 1 Expression ». Journal of Virology 83, n^o 10 (11 mars 2009) : 4749–56. http://dx.doi.org/10.1128/jvi.02585-08.

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ABSTRACT Silencing of the integrated human immunodeficiency virus type 1 (HIV-1) genome in resting CD4+ T cells is a significant contributor to the persistence of infection, allowing the virus to evade both immune detection and pharmaceutical attack. Nonselective histone deacetylase (HDAC) inhibitors are capable of inducing expression of quiescent HIV-1 in latently infected cells. However, potent global HDAC inhibition can induce host toxicity. To determine the specific HDACs that regulate HIV-1 transcription, we evaluated HDAC1 to HDAC11 RNA expression and protein expression and compartmentalization in the resting CD4+ T cells of HIV-1-positive, aviremic patients. HDAC1, -3, and -7 had the highest mRNA expression levels in these cells. Although all HDACs were detected in resting CD4+ T cells by Western blot analysis, HDAC5, -8, and -11 were primarily sequestered in the cytoplasm. Using chromatin immunoprecipitation assays, we detected HDAC1, -2, and -3 at the HIV-1 promoter in Jurkat J89GFP cells. Targeted inhibition of HDACs by small interfering RNA demonstrated that HDAC2 and HDAC3 contribute to repression of HIV-1 long terminal repeat expression in the HeLa P4/R5 cell line model of latency. Together, these results suggest that HDAC inhibitors specific for a limited number of class I HDACs may offer a targeted approach to the disruption of persistent HIV-1 infection.

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Masselli, Elena, Lilian Varricchio, Barbara Ghinassi, Carolyn Whitsett, Patricia A. Shi et Anna Rita F. Migliaccio. « Class IIa HDAC Inhibitors Reduce HDAC1 Activity by off-Target Effects Which Reduce GATA1 Expression In Human Erythroblasts Expanded Ex-Vivo ». Blood 116, n^o 21 (19 novembre 2010) : 4780. http://dx.doi.org/10.1182/blood.v116.21.4780.4780.

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Abstract Abstract 4780 Histone deacetylation maintains chromatin in a condensed configuration preventing gene expression in eukaryotic cells. The deacetylation reaction is catalyzed by enzymes of the histone deacetylase (HDAC) superfamily, which perform their functions as multiprotein complexes including at least 2 HDAC isoforms, DNA docking factors (transcription factors and methyl-binding proteins) and protein kinases (PKC and Erk). The well established role of HDACs in gene silencing has suggested studies to identify HDAC inhibitors (HDACi) that, by re-activating γ-globin expression, might treat the anemia due to insufficient β-globin expression (Cao et al Blood 103:701, 2004). Over the years several HDACi have been documented to induce γ-globin expression in human erythroid cultures, adult baboons, and β-thalassemia and sickle cell patients. Among those, Class I HDACi, and in particular those that inhibit HDAC3, appear to be more potent as γ-globin gene activators (Mankidy et al, Blood 108:3179, 2006). We have recently identified two new HDACi (compound 9 and 24) which both improved maturation and reactivated γ-globin expression in β°-thalassemic erythroblasts in vitro (Mai et al Mol Pharmacol 72:111, 2007). Compound 24 inhibits both class I (HDAC1 ID50 =0.2 μ M) and class IIa (HDAC4 ID50=0.6 μ M) HDAC. Compound 9 is a class IIa specific inhibitor (HDAC4 ID50=20 μ M) and does not affect HDAC1 activity but is a more potent γ-globin inducer than compound 24. This observation suggests that HDACi may also affect HDAC activity through indirect effects which alter overall complex activity. To clarify possible off-target effects of Class II and Class I/IIa inhibitors and their consequences for erythroid maturation, we analysed expression and activity of different HDAC isoforms during maturation of normal human erythroblasts in vitro at baseline and with treatment with compounds 9 and 24. The proteins studied included GATA1 (the major transcription regulator of erythroid maturation), p21/p27kip1, two cyclin D dependent kinase inhibitors which favor maturation, Caspase 3 (the protease which specifically cleaves GATA1) and Erk (a component of the HDAC complex). During normal erythroid maturation (without HDACi), all the HDAC isoforms were expressed at the mRNA and protein levels. Immunoprecipitation studies followed by determination of HDAC activity indicated that the activities which changed most during maturation are those of HDAC1 (class I), increased by 2-fold, and HDAC5 (class IIa), decreased by 2-fold. In addition, co-immunoprecipitation studies revealed an increase in the association between HDAC1 and GATA1 with erythroid maturation. Changes in the expression of key regulatory proteins were observed with normal erythroid maturation: activation of Caspase 3 decreased with resultant increase in GATA-1, and phosphorylation of pErk decreased while expression of p21 and p27 increased. With exposure to increasing HDACi concentrations (0.2, 2 and 6 μ M), there were class-specific, concentration-dependent alterations in protein expression: compound 9 (Class IIa inhibitor) induced Caspase 3 activation and reduced GATA1 content, while compound 24 decreased Caspase3 activation and greatly increased GATA1 content. In addition, compound 9 did not induce Erk phosphorylation and decreased p21 expression, while compound 24 did induce Erk phosphorylation and inhibited p27 expression (see figure). These results confirm the hypothesis that, in addition to class I inhibitors that directly inhibit class I HDAC, class II HDACi can also affect class I HDAC activity, through indirect effects that involve other components of the complex (repression of GATA1 expression and decrease of Erk phosphorylation). Disclosures: No relevant conflicts of interest to declare.

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Ibrahim, Hany S., Mohamed Abdelsalam, Yanira Zeyn, Matthes Zessin, Al-Hassan M. Mustafa, Marten A. Fischer, Patrik Zeyen et al. « Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity ». International Journal of Molecular Sciences 23, n^o 1 (29 décembre 2021) : 369. http://dx.doi.org/10.3390/ijms23010369.

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Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.

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Angiolilli, Chiara, Pawel A. Kabala, Aleksander M. Grabiec, Iris M. Van Baarsen, Bradley S. Ferguson, Samuel García, Beatriz Malvar Fernandez et al. « Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes ». Annals of the Rheumatic Diseases 76, n^o 1 (25 juillet 2016) : 277–85. http://dx.doi.org/10.1136/annrheumdis-2015-209064.

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ObjectivesNon-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS).MethodsRA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays.ResultsHDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11.ConclusionsInhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.

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Thèses sur le sujet "HDAC 3"

Mehdipour, P. « DISSECTING THE ROLE OF HISTONE DEACETYLASE 3 (HDAC3) IN LEUKEMOGENESIS ». Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/356617.

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Histone deacetylases (HDACs) are epigenetic enzymes that modulate chromatin structure through the deacetylation of lysine residues in histones, playing a crucial role in cell viability, cell cycle progression and tumorigenesis. Yet the role of individual HDACs in these biological processes remains enigmatic. Inappropriate recruitment of HDACs is involved in the pathogenesis of several forms of leukemia and several lines of evidence point to a role for HDACs in tumor progression, consistent with the anti-proliferative and apoptotic effects of HDAC inhibitors (HDACi). In this regard, HDACs are considered promising targets for development of new molecules for cancer therapy. To date, some HDACi which have a broad antitumor activity and low toxicity towards normal cells, such as Romidepsin (Depsipeptide or FK228) and SAHA have been approved by U.S. food and drug administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL). Moreover, HDACi are undergoing clinical trials for the treatment of hematological malignancies as well as for solid tumors. Most of the HDACi available at the moment are not isoform specific, being active on more than one HDAC. Thus, to design more selective HDACi for cancer therapy it is important to elucidate the role of individual HDACs. Acute Promyelocytic Leukemia (APL) is the first model disease in which the involvement of HDACs has been documented. APL is a subtype of Acute Myeloid Leukemia (AML), a cancer of blood and bone marrow, which is characterized by hyperproliferation of immature granulocytes blocked at the promyelocytic stage. It is genetically associated with a chromosomal translocation t(15;17)(q22;q21), which encodes the oncogenic fusion protein PML-RARα found in more than 90% of APL patients. In murine models of APL that recapitulate the human disease, PML-RARα induces a “pre-leukemic” stage with long latency and without an overtly dramatic phenotype before full leukemic transformation. In fact, for this reason it is assumed that in addition to this oncogenic fusion protein, other genetic hits are required for clonal expansion of leukemic blasts. This fusion protein recruits a number of chromatin modifier enzymes such as HDACs and DNA methyltransferases (DNMTs) to the promoter of retinoic acid (RA) target genes and transcriptionally silence them, leading to the myeloid differentiation block. Furthermore, PML-RARα causes the impairment of p53 pathway by deacetylation and degradation of p53 through the recruitment of HDAC- containing complexes. HDACs from class I (HDACs 1, 2 and 3) have been found associated with PML-RARα paving the way for the use of HDACi for APL treatment. Recently, a study on APL, which has been conducted by Santoro et al., showed that among class I HDACs, HDAC1 and to a lesser extent HDAC2 have a dual role in APL development and maintenance. In fact, while they behave as oncosuppressors at the early stages, they function as oncogenes in established tumor cells. Since inhibition of HDAC1 and HDAC2 in pre-leukemic stage leads to the acceleration of the disease in murine models of leukemia, it suggests caution in the clinical utility of epidrugs that target any of these two HDAC isoforms. Moreover, it has been shown that the expression of HDAC3, which associates with nuclear hormone corepressor and silencing mediator of retinoid hormone (NCoR/SMRT) complex, is frequently increased in tumors, while Hdac3 downregulation results in reduced proliferation and survival of tumor cells. In view of these observations, in this study we functionally assessed the role of HDAC3 in the development and maintenance of APL. To achieve our goal, we have dissected the role of HDAC3 in two different phases of the disease: pre-leukemic phase and full-established leukemia. The murine model of APL, which we used, is the mCGPR/PR mouse model in which PML-RARα is expressed under the control of the cathepsin G promoter. The mice show a very long latency (the pre-leukemic phase) associated with high penetrance (more than 90% of the mice develop APL). We characterized the role of HDAC3 through a functional knock-down approach, assessing its impact on cellular differentiation, proliferation and the ability to influence the transplantation of HSCs and APL cells. Indeed, Hdac3-KD in vitro reduced the proliferative potential of both pre-leukemic and full leukemic cells and boosted their differentiation, suggesting that HDAC3 plays the role of an oncogene in APL initiation and progression. These results were not restricted to APL, because lymphoma driven by c-myc overexpression and leukemia driven by MLL-AF9, were both impaired in cell growth upon Hdac3-KD. In vivo, inoculation of Hdac3-KD pre-leukemic cells into lethally irradiated recipient mice or inoculation of Hdac3-KD APL cells into the recipient mice did not result in leukemia development or progression, respectively. These results suggest that HDAC3 can be considered as a target for epidrugs in the treatment of hematological malignancies. Thus, we assessed this hypothesis with the treatment of pre-leukemic and leukemic cells with the HDAC3 selective inhibitor, RGFP966. Indeed, inhibition of HDAC3 enzymatic activity with RGFP966, phenocopied Hdac3-KD phenotypes in pre-leukemic and leukemic cells confirming the putative oncogenic role of HDAC3. In conclusion, my PhD project has expanded our comprehension about the role of HDAC3 in hematological malignancies and is beginning to unravel alternative views on the targets of epidrugs for the treatment of leukemic patients.

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Saglam, Guluzar. « Synthesis Of Novel Chiral Thiourea Derivatives And Their Applications, Synthesis Of Some Hdac Inhibitors, Addition Of Acyl Phosphonates To Ethylcyanoformate ». Master's thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/3/12609265/index.pdf.

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The thiourea derivatives have become a main focus of research in asymmetric synthesis as an organocatalyst in recent years. In the first part, the thiourea catalysts are synthesized starting from easily available L-tartaric acid and application of the catalysts to some addition reactions showed no significant asymmetric induction. A number of HDAC inhibitors have been developed as anti-cancer agent at the present time.In the second part, some aryl butenoic acid derivatives are synthesized as HDAC inhibitors starting from substituted benzaldehyde and pyruvic acid. The HDAC activity studies showed comparable results with known molecules. In the last part, some acyl phosphonates are synthesized and addition of ethylcyanoformate to acyl phosphonates furnished the products in good yields.

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Palleti, Janardhan Harish P. « Histone Deacetylase 3 (HDAC3) Regulates Lymphatic Vascular Development ». eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/1001.

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Cardiovascular disease continues to be the leading cause of morbidity and mortality worldwide with an estimated 17 million annual deaths. A majority of cases are attributed to disease affecting the vascular system including arterial, venous and lymphatic vessels. Despite progress in understanding the molecular bases of vascular development and disease, the role of chromatin modifying enzymes in vascular processes remains ill defined. Here we show that the histone-modifying enzyme Hdac3 is a critical regulator of lymphatic vascular development. Endothelial specific loss of Hdac3 in mice affects the development of lymphovenous and lymphatic valves resulting in aberrant blood lymph separation, lymphedema and complete lethality. We demonstrate that Hdac3 functions in a flow responsive manner to regulate the expression of Gata2, a transcription factor essential for lymphatic valve development. In response to flow, transcription factors Tal1, Ets1/2 and Gata2 recruit Hdac3 to an evolutionarily conserved intragenic enhancer of Gata2 gene. In turn, Hdac3 recruits p300, a histone acetyl transferase, to render activation of the Gata2 enhancer, and thus promotes Gata2 transcription. Together, our findings demonstrate the molecular basis by which cell extrinsic and intrinsic cues cooperate to regulate lymphatic development.

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Gao, Chengzhuo. « Mechanisms Underlying the Regulation and Functions of HDAC7 ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1213890889.

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Mortenson, Jeffrey Benjamin. « Histone Deacetylase 6 (HDAC6) Is Critical for Tumor Cell Survival and Promotes the Pro-Survival Activity of 14-3-3ζ viaDeacetylation of Lysines Within the14-3-3ζ Binding Pocket ». BYU ScholarsArchive, 2015. https://scholarsarchive.byu.edu/etd/5568.

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Our understanding of non-histone acetylation as a means of cellular regulation is in its infancy. Using a mass spectrometry approach we identified acetylated lysine residues and monitored acetylation changes across the proteome as a consequence of metabolic stress (hypoxia). We observed changes in acetylation status of non-histone lysines in tumor cells. Through the use of small molecule inhibitors of histone deacetylase enzymes (HDACs) and siRNA screening identified HDAC6 as a pro-survival regulator of lysine acetylation during hypoxia. The phospho-binding protein 14-3-3ζ acts as a signaling hub controlling a network of interacting partners and oncogenic pathways. We show here that lysines within the 14-3-3ζ binding pocket and protein-protein interface can be modified by acetylation. The positive charge on two of these lysines, K49 and K120, is critical for coordinating 14-3-3ζ-phosphoprotein interactions. Through screening, we identified HDAC6 as the K49/K120 deacetylase. Inhibition of HDAC6 blocks 14-3-3ζ interactions with two well-described interacting partners, Bad and AS160, which triggers their dephosphorylation at S112 and T642, respectively. Expression of an acetylation-refractory K49R/K120R mutant of 14-3-3ζ rescues both the HDAC6 inhibitor-induced loss of interaction and S112/T642 phosphorylation. Furthermore, expression of the K49R/K120R mutant of 14-3-3ζ inhibits the cytotoxicity of HDAC6 inhibition. These data demonstrate a novel role for HDAC6 in controlling 14-3-3ζ binding activity.

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Sargeant, Aaron Matthew. « Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer ». The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876.

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Polášek, Jaromír. « Implementace protokolu HDLC v síťových simulátorech ». Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2018. http://www.nusl.cz/ntk/nusl-377008.

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This diploma thesis deals with the possibility of using HDLC (High-Level Data Link Control) protocol for communication and addressing of smart metering devices with a data concentrator. The HDLC protocol is used in two DLMS/COSEM (Device Language Message Specification/Companion Specification for Energy Metering) communication profiles. To simulate these communication profiles, the most appropriate simulation program is selected. Using this simulator, the first communication profile is implemented and the second one is designed. Communication profile based on TCP/IP (Transmission Control Protocol/Internet Protocol) has been fully implemented. To implement the three-layer HDLC communication profile, all options have been thoroughly explored. Using these findings, a process was designed to guide the full implementation. For the first communication profile the qualitative parameters are measured, which are then plotted and evaluated.

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Wright, Lyndsey Claire. « Analysis of the physiological role of histone deacetylase 3 (HDAC3) and its regulation by inositol phosphates ». Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/40315.

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Histone deacetylase 3 (HDAC3) acts as the catalytic core of the SMRT/NCoR co-repressor complex which regulates chromatin structure and gene expression. It was recently shown that HDAC3 binds, and is regulated in vitro, by the binding of inositol phosphates (IP). We used transcriptional reporter assays to interrogate whether HDAC3-mediated repression in vivo is dependent of IP. Manipulation of intracellular IP levels through chemical inhibition of enzymes involved in IP metabolism or RNAi-mediated protein knockdown were inconclusive. However, mutation of key IP binding residues in both SMRT and HDAC3 directly impacts the repressive ability of the co-repressor complex, presumably through an impaired ability to bind IP and failure to fully activate the enzyme. Germline deletion of HDAC3 in the mouse results in early embryonic lethality (around e9.5) suggesting it plays an essential role in embryogenesis. To further investigate the role of HDAC3 in embryonic development, I have generated a conditional knockout embryonic stem cell line in which HDAC3 can be specifically inactivated. Loss of the protein occurs within 3 days suggesting a half-life of approximately 24 hours and correlates with concomitant decrease in co-repressor complex components, indicating HDAC3 contributes to co-repressor integrity. Unlike deletion of HDAC1 and -2, loss of HDAC3 does not cause a significant reduction in total deacetylase activity with only minor changes in the acetylation levels of histones. However, the proliferative capacity of knockout cells is inhibited with a delay in cell doubling time. Upon differentiation, we find that embryoid bodies (EBs) lacking HDAC3 are significantly smaller and morphologically different compared to controls. Microarray analysis over a 7-day time course of EB differentiation reveals that endodermal cell markers are over-expressed at both early and late stages of development, suggesting that HDAC3 plays an important role in regulating gene expression during embryonic development.

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BONANOMI, MARCELLA. « Normal and pathogenic ataxin-3 : biological roles, toxicity and fibrillogenesis ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50225.

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Ataxin-3 (AT3) is a deubiquitinating enzyme that triggers the inherited neurodegenerative disorder spinocerebellar ataxia type 3 when its polyglutamine (polyQ) stretch close to the C-terminus exceeds a critical length. It consists of the N-terminal globular Josephin domain (JD) and the C-terminal disordered one. Regarding its physiological role, it has ubiquitin hydrolase activity implicated in the function of the ubiquitin-proteasome system, but also plays a role in the pathway that sorts aggregated protein to aggresomes via microtubules. In the first part of this work, we further investigated its function(s) by taking advantage of Small Angle X-ray Scattering (SAXS) and Surface Plasmon Resonance (SPR). We demonstrated that an AT3 oligomer consisting of 6-7 subunits tightly binds to the tubulin hexameric oligomer at the level of three distinct tubulin-binding regions, one located in the JD, and the two others in the disordered domain, upstream and downstream of the polyQ stretch. By SPR we have also provided the first evidence of direct binding of AT3 to HDAC6, one of the components of the transport machinery that sorts protein to the aggresome. In the second part of this work, we have investigated the mechanisms of AT3 cytotoxicity triggered by expanded variants. For this purpose, we used Saccharomyces cerevisiae as a eukaryotic cellular model. We expressed a wild type (Q26), a pathogenic (Q85) and a truncated (291Δ) variant of the protein. The expanded form caused reduction in viability, accumulation of reactive oxygen species, imbalance of the antioxidant defense system and loss in cell membrane integrity. An AT3 variant truncated upstream of the polyQ also exerted a detrimental effect on cell growth and similar cytotoxicity, although to a lesser extent, which points to the involvement of also non-polyQ regions in cytotoxicity. Finally, we sought to evaluate the effects of tetracycline and epigallocatechin-3-gallate (EGCG), two well-known inhibitors of amyloid aggregation, on AT3 fibrillogenesis and cytotoxicity. We observed that tetracycline does not apparently change the aggregation mode, as supported by Fourier Transform Infrared spectroscopy and Atomic Force Microscopy data, but slightly retards further aggregation of the earliest soluble oligomers. In contrast, EGCG apparently increases the aggregation rate but also leads to the formation of off-pathway, non-amyloid, final aggregates. Despite these different effects, co-incubation of the AT3 with either compounds resulted in significantly lower cytotoxicity during AT3 aggregation.

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Lewandowski, Sara L. « Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles in Cardiac Progenitor Cells ». eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/883.

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Disruptions in cardiac development cause congenital heart disease, the most prevalent and deadly congenital malformation. Genetic and environmental factors are thought to contribute to these defects, however molecular mechanisms remain largely undefined. Recent work highlighted potential roles of chromatin- modifying enzymes in congenital heart disease pathogenesis. Histone deacetylases, a class of chromatin-modifying enzymes, have developmental importance and recognized roles in the mature heart. This thesis aimed to characterize functions of Hdac3 in cardiac development. We found loss of Hdac3 in the primary heart field causes precocious progenitor cell differentiation, resulting in hypoplastic ventricular walls, ventricular septal defect, and mid- gestational lethality. In primary heart field progenitors, Hdac3 interacts with, deacetylates, and functionally suppresses transcription factor Tbx5. Furthermore, a disease-associated Tbx5 mutation disrupts this interaction, rendering Tbx5 hyperacetylated and hyperactive. By contrast, deletion of Hdac3 in second heart field progenitors bypasses these defects, instead causing malformations in the outflow tract and semilunar valves, with lethality prior to birth. Affected semilunar valves and outflow tract vessels exhibit extracellular matrix and EndMT defects and activation of the Tgfβ1 signaling pathway. In normal second heart field development, Hdac3 represses Tgfβ1 transcription, independent of its deacetylase activity, by recruiting the PRC2 methyltransferase complex to methylate the Tgfβ1 promoter. Importantly, knockouts of Hdac3 in differentiated cardiac cells do not fully recapitulate the progenitor-specific knockout phenotypes. These results illustrate spatiotemporal roles of Hdac3, both deacetylase-dependent and deacetylase-independent, in cardiac development, suggesting that dysregulation of Hdac3 in cardiac progenitor cells could be a contributing factor in congenital heart disease pathogenesis.

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Chapitres de livres sur le sujet "HDAC 3"

Ito, Akihiro, Norikazu Nishino et Minoru Yoshida. « HDAC Inhibitors ». Dans Histone Deacetylases, 271–97. Totowa, NJ : Humana Press, 2006. http://dx.doi.org/10.1385/1-59745-024-3:271.

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Kwon, Paul, Meier Hsu, Dalia Cohen et Peter Atadja. « HDAC Inhibitors ». Dans Histone Deacetylases, 315–32. Totowa, NJ : Humana Press, 2006. http://dx.doi.org/10.1385/1-59745-024-3:315.

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Schwab, Manfred. « HDAC Inhibitors ». Dans Encyclopedia of Cancer, 1. Berlin, Heidelberg : Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_2591-2.

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Unger, Keith R., Mira Jung et Anatoly Dritschilo. « Histone Deacetylases (HDAC) ». Dans Cancer Therapeutic Targets, 1–11. New York, NY : Springer New York, 2015. http://dx.doi.org/10.1007/978-1-4614-6613-0_10-3.

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Vaquero, Alejandro, Michael Scher et Danny Reinberg. « Biochemistry of Multiprotein HDAC Complexes ». Dans Histone Deacetylases, 23–60. Totowa, NJ : Humana Press, 2006. http://dx.doi.org/10.1385/1-59745-024-3:23.

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Atadja, Peter W. « HDAC Inhibitors and Cancer Therapy ». Dans Epigenetics and Disease, 175–95. Basel : Springer Basel, 2010. http://dx.doi.org/10.1007/978-3-7643-8989-5_9.

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Kronlage, Mariya, Hugo A. Katus et Johannes Backs. « HDAC Signaling Networks in Heart Failure ». Dans Epigenetics in Cardiac Disease, 191–208. Cham : Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-41457-7_8.

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Ahmad Ganai, Shabir. « Natural Cyclic Tetrapeptide Histone Deacetylase Inhibitors and Their Optimistic Role in Anticancer Therapy ». Dans Natural HDAC Inhibitors for Epigenetic Combating of Cancer Progression, 23–29. New York : CRC Press, 2022. http://dx.doi.org/10.1201/9781003294863-3.

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Hancock, Wayne W. « Rationale for HDAC Inhibitor Therapy in Autoimmunity and Transplantation ». Dans Histone Deacetylases : the Biology and Clinical Implication, 103–23. Berlin, Heidelberg : Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-21631-2_6.

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Trifunović, Dragana, Eleni Petridou, Antonella Comitato, Valeria Marigo, Marius Ueffing et François Paquet-Durand. « Primary Rod and Cone Degeneration Is Prevented by HDAC Inhibition ». Dans Retinal Degenerative Diseases, 367–73. Cham : Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-75402-4_45.

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Actes de conférences sur le sujet "HDAC 3"

Yang, Jiyong, Chintan Chheda, Dina Hauptschein, Latifa Zayou, Josiah Tang, Qiang Wang, Stephen J. Pandol et Mouad Edderkaoui. « Abstract 2735 : Targeting HDAC prevents smoking-induced pancreatic cancer metastasis ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2735.

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Li, Mengxing, Suryavathi Viswanadhapalli, Gangadhara Reddy Sareddy, Bindu Santhamma, Hui Yan, Zhenming Xu, Edward Kost et al. « Abstract 4316 : Targeting LIFR overcomes HDAC inhibitor resistance in ovarian cancer ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4316.

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Nerlakanti, Niveditha, Jeremy McGuire, Diana Yu, Damon R. Reed et Conor C. Lynch. « Abstract 2016 : HDAC inhibition significantly reduces primary and lung metastatic osteosarcoma progression ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2016.

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Budka, Justin, Nur Damayanti et Roberto Pili. « Abstract 2366 : HDAC inhibition improves immune checkpoint inhibitor efficacy in renal cell carcinoma ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-2366.

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Wu, Bocheng. « Abstract 24 : Novel STAT3 & ; HDAC inhibitors that selectively target triple-negative breast cancer cell ». Dans Proceedings : AACR Annual Meeting 2019 ; March 29-April 3, 2019 ; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-24.

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Rapports d'organisations sur le sujet "HDAC 3"

Pignataro, C., et M. Townsley. High-Level Data Link Control (HDLC) Frames over Layer 2 Tunneling Protocol, Version 3 (L2TPv3). RFC Editor, février 2006. http://dx.doi.org/10.17487/rfc4349.

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Gur, Amit, Edward Buckler, Joseph Burger, Yaakov Tadmor et Iftach Klapp. Characterization of genetic variation and yield heterosis in Cucumis melo. United States Department of Agriculture, janvier 2016. http://dx.doi.org/10.32747/2016.7600047.bard.

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Project objectives: 1) Characterization of variation for yield heterosis in melon using Half-Diallele (HDA) design. 2) Development and implementation of image-based yield phenotyping in melon. 3) Characterization of genetic, epigenetic and transcriptional variation across 25 founder lines and selected hybrids. The epigentic part of this objective was modified during the course of the project: instead of characterization of chromatin structure in a single melon line through genome-wide mapping of nucleosomes using MNase-seq approach, we took advantage of rapid advancements in single-molecule sequencing and shifted the focus to Nanoporelong-read sequencing of all 25 founder lines. This analysis provides invaluable information on genome-wide structural variation across our diversity 4) Integrated analyses and development of prediction models Agricultural heterosis relates to hybrids that outperform their inbred parents for yield. First generation (F1) hybrids are produced in many crop species and it is estimated that heterosis increases yield by 15-30% globally. Melon (Cucumismelo) is an economically important species of The Cucurbitaceae family and is among the most important fleshy fruits for fresh consumption Worldwide. The major goal of this project was to explore the patterns and magnitude of yield heterosis in melon and link it to whole genome sequence variation. A core subset of 25 diverse lines was selected from the Newe-Yaar melon diversity panel for whole-genome re-sequencing (WGS) and test-crosses, to produce structured half-diallele design of 300 F1 hybrids (MelHDA25). Yield variation was measured in replicated yield trials at the whole-plant and at the rootstock levels (through a common-scion grafted experiments), across the F1s and parental lines. As part of this project we also developed an algorithmic pipeline for detection and yield estimation of melons from aerial-images, towards future implementation of such high throughput, cost-effective method for remote yield evaluation in open-field melons. We found extensive, highly heritable root-derived yield variation across the diallele population that was characterized by prominent best-parent heterosis (BPH), where hybrids rootstocks outperformed their parents by 38% and 56 % under optimal irrigation and drought- stress, respectively. Through integration of the genotypic data (~4,000,000 SNPs) and yield analyses we show that root-derived hybrids yield is independent of parental genetic distance. However, we mapped novel root-derived yield QTLs through genome-wide association (GWA) analysis and a multi-QTLs model explained more than 45% of the hybrids yield variation, providing a potential route for marker-assisted hybrid rootstock breeding. Four selected hybrid rootstocks are further studied under multiple scion varieties and their validated positive effect on yield performance is now leading to ongoing evaluation of their commercial potential. On the genomic level, this project resulted in 3 layers of data: 1) whole-genome short-read Illumina sequencing (30X) of the 25 founder lines provided us with 25 genome alignments and high-density melon HapMap that is already shown to be an effective resource for QTL annotation and candidate gene analysis in melon. 2) fast advancements in long-read single-molecule sequencing allowed us to shift focus towards this technology and generate ~50X Nanoporesequencing of the 25 founders which in combination with the short-read data now enable de novo assembly of the 25 genomes that will soon lead to construction of the first melon pan-genome. 3) Transcriptomic (3' RNA-Seq) analysis of several selected hybrids and their parents provide preliminary information on differentially expressed genes that can be further used to explain the root-derived yield variation. Taken together, this project expanded our view on yield heterosis in melon with novel specific insights on root-derived yield heterosis. To our knowledge, thus far this is the largest systematic genetic analysis of rootstock effects on yield heterosis in cucurbits or any other crop plant, and our results are now translated into potential breeding applications. The genomic resources that were developed as part of this project are putting melon in the forefront of genomic research and will continue to be useful tool for the cucurbits community in years to come.

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