The Experts below are selected from a list of 2988 Experts worldwide ranked by ideXlab platform
Mitchell A Lazar - One of the best experts on this subject based on the ideXlab platform.
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deletion of Histone Deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion
Molecular metabolism, 2017Co-Authors: Jarrett R Remsberg, Benjamin N Ediger, Wesley Y Ho, Manashree Damle, Zhenghui Li, Christopher Teng, Cristina Lanzillotta, Doris A Stoffers, Mitchell A LazarAbstract:Abstract Objective Histone Deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, Histone Deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. Methods An HDAC3 β-cell specific knockout was generated in adult MIP-Cre ERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and β-cell knockout islets. Results HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion. Conclusions HDAC3 plays an important role in regulating insulin secretion in vivo , and therapeutic intervention may improve glucose homeostasis.
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Histone Deacetylase 3 modulates tbx5 activity to regulate early cardiogenesis
Human Molecular Genetics, 2014Co-Authors: Sara L Lewandowski, Harish P Janardhan, Kevin M Smee, Marcos Bachman, Mitchell A Lazar, Chinmay M TrivediAbstract:Congenital heart defects often result from improper differentiation of cardiac progenitor cells. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the associated chromatin modifiers in this process remain largely unknown. Here we show that mouse embryos lacking the chromatin-modifying enzyme Histone Deacetylase 3 (Hdac3) in cardiac progenitor cells exhibit precocious cardiomyocyte differentiation, severe cardiac developmental defects, upregulation of Tbx5 target genes and embryonic lethality. Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes. These findings reveal that Hdac3 plays a critical role in cardiac progenitor cells to regulate early cardiogenesis.
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a circadian rhythm orchestrated by Histone Deacetylase 3 controls hepatic lipid metabolism
Science, 2011Co-Authors: Dan Feng, Theresa Alenghat, Shannon E Mullican, Anne Bugge, Mitchell A LazarAbstract:Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that Histone Deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of Histone acetylation and gene expression required for normal hepatic lipid homeostasis.
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the interaction between nuclear receptor corepressor and Histone Deacetylase 3 regulates both positive and negative thyroid hormone action in vivo
Molecular Endocrinology, 2010Co-Authors: Xiao Hui Liao, Roy E Weiss, Mitchell A LazarAbstract:Thyroid hormone (TH) plays a critical role in development, growth, and metabolism by binding to nuclear TH receptors to modulate gene expression. In the absence of TH, TH receptors repress genes that are TH-activated by recruiting the nuclear receptor corepressor (NCoR), which exists in a tight complex with Histone Deacetylase 3 (HDAC3). Here we explored the actions of TH in the Deacetylase activating domain mutant (DADm) mouse, whose NCoR-HDAC3 interaction is genetically disrupted. Several TH-activated genes were derepressed in the liver of euthyroid and hypothyroid DADm mice, consistent with the corepressor paradigm and a critical role of the NCoR-HDAC3 interaction in basal repression. The role of corepressors in genes that are down-regulated by TH is less well understood. Remarkably, circulating TSH levels were increased in euthyroid DADm mice, and the pituitary expression of TSHα, a classic TH-down-regulated gene, was modestly but significantly elevated regardless of TH status. Thus, the NCoR interact...
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nuclear receptor corepressor and Histone Deacetylase 3 govern circadian metabolic physiology
Nature, 2008Co-Authors: Theresa Alenghat, Shannon E Mullican, Katherine Meyers, Kirstin Leitner, Adetoun Adenijiadele, Jacqueline Avila, Maja Bucan, Rexford S Ahima, Klaus H Kaestner, Mitchell A LazarAbstract:Nuclear receptor corepressor 1 (Ncor1) is an activator for the enzyme Histone Deacetylase 3 (Hdac3) that is required for embryogenesis, but its physiological functions are unknown. Now experiments in knock-out mice lacking Ncor1 show that disruption of the Ncor1–Hdac3 interaction causes aberrant regulation of clock genes and results in abnormal circadian behaviour — with a sleep–wake cycle closer to 23 hours than the normal 24. These mice are also leaner than normal and more insulin sensitive as a result of increased energy expenditure. Loss of a functional Ncor1–Hdac3 complex in vivo changes the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Targeting of the Ncor1–Hdac3 enzyme could be a highly specific intervention in diseases of nutritional stress such as obesity and diabetes. This paper shows that specific genetic disruption of the Ncor–HdaC3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin sensitive due to increased energy expenditure. Loss of a functional Ncor–HdaC3 complex in vivo changes the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Rhythmic changes in Histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1,2,3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4,5,6,7. The nuclear receptor corepressor 1 (Ncor1) functions as an activating subunit for the chromatin modifying enzyme Histone Deacetylase 3 (Hdac3)8. Lack of Ncor1 is incompatible with life, and hence it is unknown whether Ncor1, and particularly its regulation of Hdac3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the Ncor1–Hdac3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behaviour. These mice are also leaner and more insulin-sensitive owing to increased energy expenditure. Unexpectedly, loss of a functional Ncor1–Hdac3 complex in vivo does not lead to sustained increases in known catabolic genes, but instead significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology.
Edward Seto - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 3 down regulates cholesterol synthesis through repression of lanosterol synthase gene expression
Journal of Biological Chemistry, 2007Co-Authors: Alejandro Villagra, Natalia Ulloa, Eduardo M Sotomayor, Xiaohong Zhang, Zhigang Yuan, Edward SetoAbstract:Abstract In vertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochemical functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that Histone Deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concentrations compared with parental cells. Extensive promoter analyses coupled with chromatin immunoprecipitation assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated.
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Histone Deacetylase 3 hdac3 activity is regulated by interaction with protein serine threonine phosphatase 4
Genes & Development, 2005Co-Authors: Xiaohong Zhang, Yukiyasu Ozawa, Brian E Wadzinski, Edward SetoAbstract:Histone Deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of Histones and nonHistone proteins. Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT. Here we demonstrate that, in addition to protein–protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce Deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1–122) was both necessary and sufficient for HDAC3–PP4c interactions. Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4c. These findings therefore further highlight the importance of protein–protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.
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Histone Deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4
Genes & Development, 2005Co-Authors: Xiaohong Zhang, Yukiyasu Ozawa, Brian E Wadzinski, Edward SetoAbstract:Histone Deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of Histones and nonHistone proteins. Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT. Here we demonstrate that, in addition to protein–protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce Deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1–122) was both necessary and sufficient for HDAC3–PP4c interactions. Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4c. These findings therefore further highlight the importance of protein–protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.
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Histone Deacetylase 3 Binds to and Regulates the Multifunctional Transcription Factor TFII-I
Journal of Biological Chemistry, 2002Co-Authors: W. Douglas Cress, Edward SetoAbstract:Abstract Histone Deacetylase 3 (HDAC3) is one of four members of the human class I Histone Deacetylases that are implicated in transcriptional repression through deacetylation of acetyllysines in amino-terminal tails of core Histones. In an immunoaffinity purification using anti-HDAC3, transcription factor TFII-I copurified with HDAC3. Specificity of the HDAC3-TFII-I interaction was confirmed by coimmunoprecipitation of epitope-tagged proteins, GST pull-down assays, and protein colocalization with indirect immunofluorescence. An anti-TFII-I immunoprecipitate contained Histone Deacetylase enzymatic activity. Mutational analyses revealed that the carboxyl-terminal of HDAC3 (residues 373–401) and residues 363–606 of TFII-I were required for the HDAC3-TFII-I interaction. Transcriptional activation by TFII-I was severely reduced by overexpression of HDAC3. These results suggest that HDAC3 modulates some of the functions of TFII-I and provides a link between Histone Deacetylase and a multifunctional transcriptional activator.
Xiaohong Zhang - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 3 down regulates cholesterol synthesis through repression of lanosterol synthase gene expression
Journal of Biological Chemistry, 2007Co-Authors: Alejandro Villagra, Natalia Ulloa, Eduardo M Sotomayor, Xiaohong Zhang, Zhigang Yuan, Edward SetoAbstract:Abstract In vertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochemical functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that Histone Deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concentrations compared with parental cells. Extensive promoter analyses coupled with chromatin immunoprecipitation assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated.
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Histone Deacetylase 3 hdac3 activity is regulated by interaction with protein serine threonine phosphatase 4
Genes & Development, 2005Co-Authors: Xiaohong Zhang, Yukiyasu Ozawa, Brian E Wadzinski, Edward SetoAbstract:Histone Deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of Histones and nonHistone proteins. Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT. Here we demonstrate that, in addition to protein–protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce Deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1–122) was both necessary and sufficient for HDAC3–PP4c interactions. Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4c. These findings therefore further highlight the importance of protein–protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.
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Histone Deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4
Genes & Development, 2005Co-Authors: Xiaohong Zhang, Yukiyasu Ozawa, Brian E Wadzinski, Edward SetoAbstract:Histone Deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of Histones and nonHistone proteins. Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT. Here we demonstrate that, in addition to protein–protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce Deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1–122) was both necessary and sufficient for HDAC3–PP4c interactions. Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4c. These findings therefore further highlight the importance of protein–protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.
Scott W. Hiebert - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 3 controls a transcriptional network required for B cell maturation.
Nucleic Acids Research, 2019Co-Authors: Kristy R. Stengel, Srividya Bhaskara, Jing Wang, Jacob D Ellis, Shilpa Sampathi, Scott W. HiebertAbstract:: Histone Deacetylase 3 (Hdac3) is a target of the FDA approved HDAC inhibitors, which are used for the treatment of lymphoid malignancies. Here, we used Cd19-Cre to conditionally delete Hdac3 to define its role in germinal center B cells, which represent the cell of origin for many B cell malignancies. Cd19-Cre-Hdac3-/- mice showed impaired germinal center formation along with a defect in plasmablast production. Analysis of Hdac3-/- germinal centers revealed a reduction in dark zone centroblasts and accumulation of light zone centrocytes. RNA-seq revealed a significant correlation between genes up-regulated upon Hdac3 loss and those up-regulated in Foxo1-deleted germinal center B cells, even though Foxo1 typically activates transcription. Therefore, to determine whether gene expression changes observed in Hdac3-/- germinal centers were a result of direct effects of Hdac3 Deacetylase activity, we used an HDAC3 selective inhibitor and examined nascent transcription in germinal center-derived cell lines. Transcriptional changes upon HDAC3 inhibition were enriched for light zone gene signatures as observed in germinal centers. Further comparison of PRO-seq data with ChIP-seq/exo data for BCL6, SMRT, FOXO1 and H3K27ac identified direct targets of HDAC3 function including CD86, CD83 and CXCR5 that are likely responsible for driving the light zone phenotype observed in vivo.
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Deacetylase activity of Histone Deacetylase 3 is required for productive vdj recombination and b cell development
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Kristy R. Stengel, Scott W. Hiebert, Jing Wang, Kelly R Barnett, Emily Hodges, Srividya BhaskaraAbstract:Histone Deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed Hdac3 conditional knockout mice with Mb1-Cre knockin animals to delete Hdac3 in early progenitor B cells. The spleens of Hdac3 F/− Mb1-Cre +/− mice were virtually devoid of mature B cells, and B220 + CD43 + B-cell progenitors accumulated within the bone marrow. Quantitative deep sequencing of the Ig heavy chain locus from B220 + CD43 + populations identified a defect in V H DJ H recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from Hdac3 Δ /− bone marrow. For Hdac3 Δ /− B cells that did show productive VDJ rearrangement, there was significant skewing toward the incorporation of proximal V H gene segments and a corresponding reduction in distal V H gene segment use. Although transcriptional effects within these loci were modest, Hdac3 Δ /− progenitor cells displayed global changes in chromatin structure that likely hindered effective distal V-DJ recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking Deacetylase activity failed to complement this defect. Thus, the Deacetylase activity of Hdac3 is required for the generation of mature B cells.
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Histone Deacetylase 3 is required for t cell maturation
Journal of Immunology, 2015Co-Authors: Paul J Belmonte, Scott W. Hiebert, Megan M Constans, Meibo W Chen, Douglas C Mcwilliams, Virginia Smith ShapiroAbstract:Recent thymic emigrants are newly generated T cells that need to undergo postthymic maturation to gain functional competency and enter the long-lived naive T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. Because NKAP associates with Histone Deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. Although thymic populations are similar in CD4-cre HDAC3 conditional knockout mice compared with wild-type mice, the peripheral numbers of CD4 + and CD8 + T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naive T cells are recent thymic emigrants, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 conditional knockout mice do not have a defect in intrathymic migration, thymic egress, T cell survival, or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.
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Role for Histone Deacetylase 3 in maintenance of genome stability.
Cell Cycle, 2011Co-Authors: Srividya Bhaskara, Scott W. HiebertAbstract:Histone Deacetylase 3 (Hdac3) is the catalytic enzyme in a transcriptional repression complex that contains the nuclear hormone co-repressors (N-CoR or SMRT). As such, Hdac3 has largely been studied in the context of gene regulation of targets of nuclear hormone receptors and other transcription factors that recruit these corepressors. However, gene deletion studies in mice have shed new light on potential cell cycle roles of this Histone Deacetylase complex. Because of the roles of nuclear hormone signaling pathways in metabolism, the physiological roles of Hdac3 and its activating factors NCOR and SMRT are of great interest. But just as important as its roles in metabolism, is the recruitment of this repression complex by oncogenic transcription factors such as BCL6. In fact, Hdac3 may be a key target of Vorinostat and Romidepsin, two drugs approved by the FDA for use in cutaneous T-cell lymphoma. These roles in metabolism and cancer have spurred the genetic analysis of Hdac3 deficiency in mice. Deletion of Hdac3 in the germ line led to very early embryonic lethality. Surprisingly, when the Cre-loxP system was used to delete Hdac3 in mouse embryo fibroblasts (MEFs), apoptosis was induced with a delayed progression of cells through S phase and an increase in S phase-associated Histone acetylation marks (H4K5ac and H4K12ac). Also, loss of Hdac3 triggered DNA damage, which required cell cycle progression, as no DNA damage was observed in Hdac3 MEFs after serum starvation. Similar results were found after treatment with SAHA (Vorinostat), suggesting that the cell cycle-dependent DNA damage contributes to the therapeutic window of HDIs. Role for Histone Deacetylase 3 in maintenance of genome stability
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liver specific deletion of Histone Deacetylase 3 disrupts metabolic transcriptional networks
The EMBO Journal, 2008Co-Authors: Sarah K Knutson, Srividya Bhaskara, Brenda J Chyla, Joseph M Amann, Stacey S Huppert, Scott W. HiebertAbstract:Histone Deacetylase 3 (Hdac3) is an enzymatic component of transcriptional repression complexes recruited by the nuclear hormone receptors. Inactivation of Hdac3 in cancer cell lines triggered apoptosis, and removal of Hdac3 in the germ line of mice caused embryonic lethality. Therefore, we deleted Hdac3 in the postnatal mouse liver. These mice developed hepatomegaly, which was the result of hepatocyte hypertrophy, and these morphological changes coincided with significant imbalances between carbohydrate and lipid metabolism. Loss of Hdac3 triggered changes in gene expression consistent with inactivation of repression mediated by nuclear hormone receptors. Loss of Hdac3 also increased the levels of Pparγ2, and treatment of these mice with a Pparγ antagonist partially reversed the lipid accumulation in the liver. In addition, gene expression analysis identified mammalian target of rapamycin signalling as being activated after deletion of Hdac3, and inhibition by rapamycin affected the accumulation of neutral lipids in Hdac3-null livers. Thus, Hdac3 regulates metabolism through multiple signalling pathways in the liver, and deletion of Hdac3 disrupts normal metabolic homeostasis.
Jiujiu Yu - One of the best experts on this subject based on the ideXlab platform.
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the Histone binding code of nuclear receptor co repressors matches the substrate specificity of Histone Deacetylase 3
EMBO Reports, 2005Co-Authors: Helen B Hartman, Theresa Alenghat, Jiujiu Yu, Takahiro Ishizuka, Mitchell A LazarAbstract:Ligands for nuclear receptors facilitate the exchange of co-repressors for coactivators, leading to chromatin modifications that favour the activation of gene transcription. Here, we show that the repressed state of an endogenous retinoic acid-regulated gene is quickly re-established after ligand removal. As expected, repression is characterized by recruitment of N-CoR/SMRT–HDAC3 (Histone Deacetylase 3) co-repressor complexes, leading to local Histone hypoacetylation. The achievement of the repressed state involves the ordered deacetylation of lysines in H4 tails. This order is determined by the inherent substrate specificity of HDAC3, and unexpectedly predicts the binding preference of N-CoR/SMRT for submaximally acetylated H4 tails. The match between the specificity of acetyl-Histone deacetylation by HDAC3 and the Histone-binding preference of N-CoR/SMRT allows the co-repressor complex to stabilize and propagate repression of nuclear hormone receptor gene targets.
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assembly of the smrt Histone Deacetylase 3 repression complex requires the tcp 1 ring complex
Genes & Development, 2002Co-Authors: Matthew G Guenther, Jiujiu Yu, Mitchell A LazarAbstract:The acetylation of Histone tails is a primary determinant of gene activity. Histone Deacetylase 3 (HDAC3) requires the nuclear receptor corepressor SMRT for HDAC enzyme activity. Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process. SMRT displaces TRiC from HDAC3, yielding an active HDAC enzyme. The SMRT–HDAC3 repression complex thus joins the VHL–elongin BC tumor suppression complex and the cyclin E–Cdk2 cell cycle regulation complex as critical cellular machines requiring TRiC for proper assembly and function. The strict control of HDAC3 activity underscores the cellular imperative that Histone deacetylation occur only in targeted regions of the genome.
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Assembly of the SMRT–Histone Deacetylase 3 repression complex requires the TCP-1 ring complex
Genes & Development, 2002Co-Authors: Matthew G Guenther, Jiujiu Yu, Mitchell A LazarAbstract:The acetylation of Histone tails is a primary determinant of gene activity. Histone Deacetylase 3 (HDAC3) requires the nuclear receptor corepressor SMRT for HDAC enzyme activity. Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process. SMRT displaces TRiC from HDAC3, yielding an active HDAC enzyme. The SMRT–HDAC3 repression complex thus joins the VHL–elongin BC tumor suppression complex and the cyclin E–Cdk2 cell cycle regulation complex as critical cellular machines requiring TRiC for proper assembly and function. The strict control of HDAC3 activity underscores the cellular imperative that Histone deacetylation occur only in targeted regions of the genome.