Cell-type-specific gene expression is physiologically modulated by the binding of transcription factors to genomic enhancer sequences, to which chromatin modifiers such as histone deacetylases (HDACs) are recruited. Drugs that inhibit HDACs are in clinical use but lack specificity. HDAC3 is a stoichiometric component of nuclear receptor co-repressor complexes whose enzymatic activity depends on this interaction. HDAC3 is required for many aspects of mammalian development and physiology, for example, for controlling metabolism and circadian rhythms. In this Review, we discuss the mechanisms by which HDAC3 regulates cell type-specific enhancers, the structure of HDAC3 and its function as part of nuclear receptor co-repressors, its enzymatic activity and its post-translational modifications. We then discuss the plethora of tissue-specific physiological functions of HDAC3.
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Gene expression omnibus: https://www.ncbi.nlm.nih.gov/gds
Ong, C.-T. & Corces, V. G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat. Rev. Genet. 12, 283–293 (2011).
Spitz, F. & Furlong, E. E. M. Transcription factors: from enhancer binding to developmental control. Nat. Rev. Genet. 13, 613–626 (2012).
Glass, C. K. & Natoli, G. Molecular control of activation and priming in macrophages. Nat. Immunol. 17, 26–33 (2016).
Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33–43 (2005).
Lefterova, M. I. et al. PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 22, 2941–2952 (2008).
Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).
John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43, 264–268 (2011).
Grøntved, L. et al. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J. 32, 1568–1583 (2013).
Madsen, M. S., Siersbæk, R., Boergesen, M., Nielsen, R. & Mandrup, S. Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading. Mol. Cell. Biol. 34, 939–954 (2014).
Soccio, R. E. et al. Genetic variation determines PPARγ function and anti-diabetic drug response in vivo. Cell 162, 33–44 (2015).
Yang, X.-J. & Seto, E. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31, 449–461 (2008).
Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16, 258–264 (2015). This is an excellent review of the role of protein acetylation in biology.
Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643 (1996).
Ogryzko, V. V., Schiltz, R. L., Russanova, V., Howard, B. H. & Nakatani, Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87, 953–959 (1996).
Yang, X. J., Ogryzko, V. V., Nishikawa, J., Howard, B. H. & Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382, 319–324 (1996).
Spencer, T. E. et al. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389, 194–198 (1997).
Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).
Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Sci. 272, 408–411 (1996).
Yang, X.-J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol. 9, 206–218 (2008).
Kadosh, D. & Struhl, K. Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo. Genes Dev. 12, 797–805 (1998).
Rundlett, S. E. et al. HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc. Natl Acad. Sci. USA 93, 14503–14508 (1996).
Gregoretti, I. V., Lee, Y. M. & Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17–31 (2004).
Lahm, A. et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl Acad. Sci. USA 104, 17335–17340 (2007).
Schwer, B. & Verdin, E. Conserved metabolic regulatory functions of sirtuins. Cell. Metab. 7, 104–112 (2008).
Chang, H.-C. & Guarente, L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab. 25, 138–145 (2014).
Chalkiadaki, A. & Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol. 8, 287–296 (2012).
Seto, E. & Yoshida, M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6, a018713 (2014).
West, A. C. & Johnstone, R. W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124, 30–39 (2014).
Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000).
Wen, Y. D. et al. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 97, 7202–7207 (2000).
Guenther, M. G. et al. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14, 1048–1057 (2000). References 29–31 identify the stoichiometric relationship between nuclear receptor co-repressors and HDAC3.
Everett, L. J. & Lazar, M. A. Cell-specific integration of nuclear receptor function at the genome. Wiley Interdiscip. Rev. Syst. Biol. Med. 5, 615–629 (2013).
Francis, G. A., Fayard, E., Picard, F. & Auwerx, J. Nuclear receptors and the control of metabolism. Annu. Rev. Physiol. 65, 261–311 (2003).
Perissi, V. & Rosenfeld, M. G. Controlling nuclear receptors: the circular logic of cofactor cycles. Nat. Rev. Mol. Cell Biol. 6, 542–554 (2005).
Hong, S. H. et al. Nuclear receptors and metabolism: from feast to famine. Diabetologia 57, 860–867 (2014).
Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).
McKenna, N. J., Lanz, R. B. & O’Malley, B. W. Nuclear receptor coregulators: cellular and molecular biology. Endocr. Rev. 20, 321–344 (1999).
Hu, X. & Lazar, M. A. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402, 93–96 (1999).
Perissi, V., Jepsen, K., Glass, C. K. & Rosenfeld, M. G. Deconstructing repression: evolving models of co-repressor action. Nat. Rev. Genet. 11, 109–123 (2010).
Yoon, H. G. et al. Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J. 22, 1336–1346 (2003).
Zhang, J., Kalkum, M., Chait, B. T. & Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Mol. Cell 9, 611–623 (2002).
Kao, H. Y., Downes, M., Ordentlich, P. & Evans, R. M. Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression. Genes Dev. 14, 55–66 (2000).
Heinzel, T. et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997).
Nagy, L. et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89, 373–380 (1997).
Huang, E. Y. et al. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev. 14, 45–54 (2000).
Perissi, V. et al. Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev. 13, 3198–3208 (1999).
Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001). This paper reports that HDAC3 activity requires nuclear receptor co-repressors.
Ishizuka, T. & Lazar, M. A. The nuclear receptor corepressor deacetylase activating domain is essential for repression by thyroid hormone receptor. Mol. Endocrinol. 19, 1443–1451 (2005).
Codina, A. et al. Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors. Proc. Natl Acad. Sci. USA 102, 6009–6014 (2005).
Aasland, R., Stewart, A. F. & Gibson, T. The SANT domain: a putative DNA-binding domain in the SWI-SNF and ADA complexes, the transcriptional co-repressor N-CoR and TFIIIB. Trends Biochem. Sci. 21, 87–88 (1996).
Boyer, L. A. et al. Essential role for the SANT domain in the functioning of multiple chromatin remodeling enzymes. Mol. Cell 10, 935–942 (2002).
Boyer, L. A., Latek, R. R. & Peterson, C. L. The SANT domain: a unique histone-tail-binding module? Nat. Rev. Mol. Cell Biol. 5, 158–163 (2004).
Yu, J., Li, Y., Ishizuka, T., Guenther, M. G. & Lazar, M. A. A. SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J. 22, 3403–3410 (2003).
Watson, P. J., Fairall, L., Santos, G. M. & Schwabe, J. W. R. Structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature 481, 335–340 (2012). This paper reports the crystal structure of HDAC3 bound to a nuclear receptor DAD, identifying crucial interactions between the two proteins and a role for IP4 in maintaining them.
You, S.-H. et al. Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo. Nat. Struct. Mol. Biol. 20, 182–187 (2013). This paper demonstrates that the enzymatic activity of HDAC3 requires nuclear receptor co-repressors in vivo.
Adrain, C. & Freeman, M. New lives for old: evolution of pseudoenzyme function illustrated by iRhoms. Nat. Rev. Mol. Cell Biol. 13, 489–498 (2012).
Guo, C. et al. Regulated clearance of histone deacetylase 3 protects independent formation of nuclear receptor corepressor complexes. J. Biol. Chem. 287, 12111–12120 (2012).
Guenther, M. G., Yu, J., Kao, G. D., Yen, T. J. & Lazar, M. A. Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex. Genes Dev. 16, 3130–3135 (2002).
Sun, Z. et al. Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor. Mol. Cell 52, 769–782 (2013). This paper describes non-enzymatic functions of HDAC3.
Bhaskara, S. et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 30, 61–72 (2008).
Montgomery, R. L. et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J. Clin. Invest. 118, 3588–3597 (2008).
Alenghat, T. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456, 997–1000 (2008). This paper is the first to demonstrate a physiological role of the NCoR1–HDAC3 complex.
Sengupta, N. & Seto, E. Regulation of histone deacetylase activities. J. Cell. Biochem. 93, 57–67 (2004).
Lonard, D. M. & O’Malley, B. W. Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol. Cell 27, 691–700 (2007).
Tsai, S.-C. & Seto, E. Regulation of histone deacetylase 2 by protein kinase CK2. J. Biol. Chem. 277, 31826–31833 (2002).
Zhang, X. et al. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev. 19, 827–839 (2005).
Knutson, S. K. et al. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 27, 1017–1028 (2008).
Villagra, A. et al. Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression. J. Biol. Chem. 282, 35457–35470 (2007).
Sun, Z. et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18, 934–942 (2012).
Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011).
Zamir, I., Zhang, J. & Lazar, M. A. Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes Dev. 11, 835–846 (1997).
Hu, X., Li, Y. & Lazar, M. Determinants of CoRNR-dependent repression complex assembly on nuclear hormone receptors. Mol. Cell. Biol. 21, 1747–1758 (2001).
Bugge, A. et al. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function. Genes Dev. 26, 657–667 (2012).
Kim, Y. H. et al. Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription. Science 359, 1274–1277 (2018).
Zhang, Y. et al. Gene regulation. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348, 1488–1492 (2015).
Armour, S. M. et al. An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides. Nat. Commun. 8, 549 (2017).
Emmett, M. J. et al. Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Nature 546, 544–548 (2017).
Enerbäck, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997).
Villena, J. A. et al. Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis. Proc. Natl Acad. Sci. USA 104, 1418–1423 (2007).
Giguère, V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr. Rev. 29, 677–696 (2008).
Luo, J. et al. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol. Cell. Biol. 23, 7947–7956 (2003).
Chang, J. S., Ghosh, S., Newman, S. & Salbaum, J. M. A map of the PGC-1α- and NT-PGC-1α-regulated transcriptional network in brown adipose tissue. Sci. Rep. 8, 7876 (2018).
Schreiber, S. N., Knutti, D., Brogli, K., Uhlmann, T. & Kralli, A. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). J. Biol. Chem. 278, 9013–9018 (2003).
Brown, E. L. et al. Estrogen-related receptors mediate the adaptive response of brown adipose tissue to adrenergic stimulation. iScience 2, 221–237 (2018).
Ahmadian, M. et al. ERRγ preserves brown fat innate thermogenic activity. Cell Rep. 22, 2849–2859 (2018).
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).
Hasegawa, Y. et al. Repression of adipose tissue fibrosis through a PRDM16-GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metab. 27, 180–194 (2018).
Berry, D. C. et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab. 25, 481 (2017).
Ferrari, A. et al. HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning. Nat. Commun. 8, 93 (2017).
Somech, R. et al. The nuclear-envelope protein and transcriptional repressor LAP2beta interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation. J. Cell Sci. 118, 4017–4025 (2005).
Vincent, S. D. & Buckingham, M. E. How to make a heart. The origin and regulation of cardiac progenitor cells. Curr. Top. Dev. Biol. 90, 1–41 (2010).
Lewandowski, S. L. et al. Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis. Hum. Mol. Genet. 23, 3801–3809 (2014).
Lewandowski, S. L., Janardhan, H. P. & Trivedi, C. M. Histone deacetylase 3 coordinates deacetylase-independent epigenetic silencing of transforming growth factor-β1 (TGF-β1) to orchestrate second heart field development. J. Biol. Chem. 290, 27067–27089 (2015).
Poleshko, A. et al. Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction. Cell 171, 573–587 (2017).
Demmerle, J., Koch, A. J. & Holaska, J. M. The nuclear envelope protein emerin binds directly to histone deacetylase 3 (HDAC3) and activates HDAC3 activity. J. Biol. Chem. 287, 22080–22088 (2012).
Zullo, J. M. et al. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 1474–1487 (2012).
Jain, R. & Epstein, J. A. Competent for commitment: you’ve got to have heart! Genes Dev. 32, 4–13 (2018).
Van Der Linde, D. et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J. Am. Coll. Cardiol. 58, 2241–2247 (2011).
Loeys, B. L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37, 275–281 (2005).
Neptune, E. R. et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).
Singh, N. et al. Histone deacetylase 3 regulates smooth muscle differentiation in neural crest cells and development of the cardiac outflow tract. Circ. Res. 109, 1240–1249 (2011).
Sun, Z. et al. Diet-induced lethality due to deletion of the Hdac3 gene in heart and skeletal muscle. J. Biol. Chem. 286, 33301–33309 (2011).
Vega, R. B. & Kelly, D. P. Cardiac nuclear receptors: architects of mitochondrial structure and function. J. Clin. Invest. 127, 1155–1164 (2017).
Finck, B. N. & Kelly, D. P. PGC-1 coactivators: Inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615–622 (2006).
Norwood, J., Franklin, J. M., Sharma, D. & D’Mello, S. R. Histone deacetylase 3 is necessary for proper brain development. J. Biol. Chem. 289, 34569–34582 (2014).
Zhang, L. et al. Hdac3 interaction with p300 histone acetyltransferase regulates the oligodendrocyte and astrocyte lineage fate switch. Dev. Cell 36, 316–330 (2016).
He, X. et al. A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. Nat. Med. 24, 338–351 (2018).
McQuown, S. C. et al. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci. 31, 764–774 (2011).
Rogge, G. A., Singh, H., Dang, R. & Wood, M. A. HDAC3 is a negative regulator of cocaine-context-associated memory formation. J. Neurosci. 33, 6623–6632 (2013).
Ebert, D. H. et al. Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341–345 (2013).
Lyst, M. J. et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902 (2013).
Nott, A. et al. Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat. Neurosci. 19, 1497–1505 (2016).
Wang, Y. et al. HDAC3-dependent epigenetic pathway controls lung alveolar epithelial cell remodeling and spreading via miR-17-92 and TGF-β signaling regulation. Dev. Cell 36, 303–315 (2016).
Wang, X. et al. Expression of histone deacetylase 3 instructs alveolar type I cell differentiation by regulating a Wnt signaling niche in the lung. Dev. Biol. 414, 161–169 (2016).
Alenghat, T. et al. Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504, 153–157 (2013).
Navabi, N. et al. Epithelial histone deacetylase 3 instructs intestinal immunity by coordinating local lymphocyte activation. Cell Rep. 19, 1165–1175 (2017).
Whitt, J. et al. Disruption of epithelial HDAC3 in intestine prevents diet-induced obesity in mice. Gastroenterology 155, 501–513 (2018).
Remsberg, J. R. et al. Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion. Mol. Metab. 6, 30–37 (2017).
Lundh, M., Galbo, T., Poulsen, S. S. & Mandrup-Poulsen, T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes. Metab. 17, 703–707 (2015).
Chou, D. H. C. et al. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem. Biol. 19, 669–673 (2012).
Lundh, M. et al. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children. Diabetologia 55, 2421–2431 (2012).
Chen, W.-B. et al. Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. Oncotarget 7, 57485–57497 (2016).
Magnuson, M. A. & Osipovich, A. B. Pancreas-specific Cre driver lines and considerations for their prudent use. Cell Metab. 18, 9–20 (2013).
Song, J., Xu, Y., Hu, X., Choi, B. & Tong, Q. Brain expression of Cre recombinase driven by pancreas-specific promoters. Genesis 48, 628–634 (2010).
Hong, S. et al. Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat. Med. 23, 223–234 (2017).
Mullican, S. E. et al. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 25, 2480–2488 (2011).
Chen, X. et al. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc. Natl Acad. Sci. USA 109, E2865–E2874 (2012).
Hoeksema, M. a et al. Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol. Med. 6, e201404170 (2014).
Bhaskara, S. et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436–447 (2010).
Summers, A. R. et al. HDAC3 is essential for DNA replication in hematopoietic progenitor cells. J. Clin. Invest. 123, 3112–3123 (2013).
Stengel, K. R. et al. Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B cell development. Proc. Natl Acad. Sci. USA 114, 8608–8613 (2017).
Stengel, K. R. et al. Histone deacetylase 3 is required for efficient T cell development. Mol. Cell. Biol. 35, 3854–3865 (2015).
Philips, R. L. et al. HDAC3 is required for the downregulation of RORγt during thymocyte positive selection. J. Immunol. 197, 541–554 (2016).
Hsu, F.-C. et al. Histone deacetylase 3 is required for T cell maturation. J. Immunol. 195, 1578–1590 (2015).
Wang, L. et al. FOXP3 + regulatory T cell development and function require histone / protein deacetylase 3. J. Clin. Invest. 125, 1–13 (2015).
Chen Lf, Fischle, W., Verdin, E. & Greene, W. C. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293, 1653–1657 (2001).
Bradley, E. W., Carpio, L. R., van Wijnen, A. J., McGee-Lawrence, M. E. & Westendorf, J. J. Histone deacetylases in bone development and skeletal disorders. Physiol. Rev. 95, 1359–1381 (2015).
Singh, N. et al. Murine craniofacial development requires Hdac3-mediated repression of Msx gene expression. Dev. Biol. 377, 333–344 (2013).
Razidlo, D. F. et al. Histone deacetylase 3 depletion in osteo/chondroprogenitor cells decreases bone density and increases marrow fat. PLOS ONE 5, e11492 (2010).
Feigenson, M. et al. Histone deacetylase 3 deletion in mesenchymal progenitor cells hinders long bone development. J. Bone Miner. Res. 32, 2453–2465 (2017).
Carpio, L. R. et al. Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. Sci. Signal. 9, ra79 (2016).
McGee-Lawrence, M. E. et al. Histone deacetylase 3 is required for maintenance of bone mass during aging. Bone 52, 296–307 (2013).
Schroeder, T. M., Kahler, R. A., Li, X. & Westendorf, J. J. Histone deacetylase 3 interacts with Runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation. J. Biol. Chem. 279, 41998–42007 (2004).
McGee-Lawrence, M. E. et al. Runx2 protein represses axin2 expression in osteoblasts and is required for craniosynostosis in axin2-deficient mice. J. Biol. Chem. 288, 5291–5302 (2013).
Hesse, E. et al. Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity. J. Cell Biol. 191, 1271–1283 (2010).
Giavini, E. & Menegola, E. Teratogenic activity of HDAC inhibitors. Curr. Pharm. Des. 20, 5438–5442 (2014).
Boluk, A. et al. The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol. Res. 50, 93–97 (2004).
Guo, C. Y., Ronen, G. M. & Atkinson, S. A. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 42, 1141–1147 (2001).
Oner, N. et al. Bone mineral metabolism changes in epileptic children receiving valproic acid. J. Paediatr. Child Health 40, 470–473 (2004).
Sato, Y. et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 57, 445–449 (2001).
Lajeunie, E. et al. Craniosynostosis and fetal exposure to sodium valproate. J. Neurosurg. 95, 778–782 (2001).
Sharony, R. et al. Preaxial ray reduction defects as part of valproic acid embryofetopathy. Prenat. Diagn. 13, 909–918 (1993).
Paradis, F.-H. & Hales, B. F. The effects of class-specific histone deacetylase inhibitors on the development of limbs during organogenesis. Toxicol. Sci. 148, 220–228 (2015).
Heinz, S. et al. Effect of natural genetic variation on enhancer selection and function. Nature 503, 487–492 (2013).
Janardhan, H. P. et al. Hdac3 regulates lymphovenous and lymphatic valve formation. J. Clin. Invest. 127, 4193–4206 (2017).
Smith, E. & Shilatifard, A. Enhancer biology and enhanceropathies. Nat. Struct. Mol. Biol. 21, 210–219 (2014).
Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 3, 429–438 (2006).
Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113–118 (2005).
Wang, W. et al. Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc. Natl Acad. Sci. USA 111, 14466–14471 (2014).
Shapira, S. N. et al. EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex. Genes Dev. 31, 660–673 (2017).
Thompson, J. A., Tan, J. & Greene, C. S. Cross-platform normalization of microarray and RNA-seq data for machine learning applications. PeerJ 4, e1621 (2016).
Ritchie, M. E. et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
The authors thank members of the Lazar laboratory for discussion and comments on the manuscript. They also thank H.-W. Lim for processing ChIP-seq and GRO-seq data from GEO data sets (GSE83928 and GSE110056), H. B. Nguyen for bioinformatics analysis of gene expression (GSE98650, GSE90531, GSE83927, GSE72917, GSE50188, GSE85929, GSE33609, GSE79696 and GSE68991) and H. J. Richter for assistance with modelling the crystal structure of HDAC3. US National Institutes of Health (NIH) grant R01 DK45586 (M.A.L.) and NIH F30 DK104513 (M.J.E.) supported this work.
Nature Reviews Molecular Cell Biology thanks C. Trivedi and the other anonymous reviewer(s) for their contribution to the peer review of this work.
- Lineage-determining transcription factors
Transcription factors that determine the differentiation fate of cells.
- Signal-dependent transcription factors
Transcription factors that associate with or bind to specific DNA sequences near lineage-determining transcription factors in response to environmental or physiological cues.
- Nuclear receptors
A superfamily of transcription factors that bind to highly specific DNA motifs in direct response to ligand binding to activate or repress gene transcription.
- Stoichiometric component
A protein whose interaction with another component of a protein complex is based on their equal molarity.
- WD40 repeat-containing proteins
Proteins containing a motif of 40 amino acids that assumes a β-propeller structure and functions in establishing protein–protein interactions, signal transduction and transcription regulation.
- Cre recombinase
(Cre). A bacteriophage P1 type I topoisomerase that catalyses DNA recombination between site-specific loxP sites.
- Adeno-associated virus
(AAV). A small, non-enveloped, replication-incompetent virus with a small single-stranded DNA genome, which is maintained extrachromosomally and used for gene delivery.
Fatty liver, often owing to the pathological accumulation of triglycerides.
- Nonshivering thermogenesis
A facultative and adaptive process that protects core body temperature.
- Oxidative phosphorylation
The transfer of electrons in mitochondria between energy carriers down the electron transport chain to generate a proton gradient and produce ATP.
- Global run-on sequencing
(GRO–seq). A nuclear run-on assay coupled to next-generation sequencing to map all transcription by engaged RNA polymerases throughout the genome.
- Futile metabolic cycles
Biochemical pathways that operate simultaneously in opposing directions, often leading to the dissipation of energy.
- First heart field
(FHF). A developmental structure that gives rise to the cardiac crescent, early cardiac tube and left ventricle.
- Second heart field
(SHF). A developmental structure that gives rise to the right ventricle, atrial myocardium and cardiac outflow tract.
- Nuclear lamina
A cellular structure adjacent to the inner nuclear membrane that is composed of lamin polymers and other proteins and forms a skeletal nuclear structure that interacts with nuclear scaffold proteins and chromatin.
- Facultative heterochromatin
Tightly packed, inaccessible chromatin containing inactive genes, which may become accessible and expressed in certain cell types or following certain cellular cues.
- Marfan syndrome
A connective tissue disorder caused by mutations in the fibrillin 1 gene, often presenting as tall, slender individuals with arachnodactyly, cardiac valve disease and predisposition to aortic aneurysm and dissection.
- Loeys–Dietz syndrome
A connective tissue disorder with five subtypes, each caused by unique mutations in five genes of the TGFβ signalling pathway, which cause congenital cardiac defects and predisposition to aortic aneurysm and dissection.
- CA1 hippocampal region
An area of the brain that is important for memory.
- Nucleus accumbens
A region of the brain that is involved in cognitive processing of reward, with neurons containing mostly dopamine receptors; the nucleus accumbens is thought to be the major nucleus involved in addiction.
- Paneth cells
Epithelial cells of the small intestine that secrete antimicrobial peptides and proteins, mediate host–microorganism interactions and help defend against enteric pathogens in the gut lumen.
- Regulatory T cells
(Treg cells). CD4+, CD25+ and FOXP3+ T cells that suppress the activation of the immune system to maintain tolerance to self-antigens and prevent autoimmune disease.
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