Integrative regulation of physiology by histone deacetylase 3

Abstract

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.

Fig. 1 |. HDAC3 is a core component of nuclear receptor co-repressor complexes that modulate nuclear receptor-mediated transcription.

a | Histone deacetylase 3 (HDAC3)-containing nuclear receptor co-repressors complexes bind to ligand-free nuclear receptors and repress transcription, partly by deacetylating histones. Ligand binding by the nuclear receptors dismisses the co-repressor complex and recruits co-activators that promote gene transcription, partly through histone acetylation. b | Crystal structure modelling (Protein Data Bank (PDB) identifier (ID): 4A69) of the HDAC3 interaction with the deacetylase-activating domain (DAD) of silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and inositol tetraphosphate (IP4) is shown. The interaction with the SMRT DAD is required for the enzymatic activity of HDAC3 (REFS^,,). Ac, acetyl group; GPS2, G protein pathway suppressor 2; H3K27ac, acetylated histone H3 lysine 27; H3K9ac, acetylated histone H3 lysine 9; NCoR, nuclear receptor co-repressor 1; NR, nuclear receptor; TBL1X, transducin β-Like 1, X-Linked; TBL1XR1, TBL1-reLated protein 1.

Fig. 2 |. HDAC3 suppresses liver metabolism and circadian clock genes through distinct enhancer complexes.

a | The circadian nuclear receptor REV-ERBα is maximally expressed in mice at Zeitgeber time (ZT) 10, during the light period, and is nearly absent 12 hours later in the dark period (at ZT 22). REV-ERBα recruits histone deacetylase 3 (HDAC3) through the nuclear receptor co-repressor 1 (NCoR) complex to its canonical DNA-binding motifs RevDR2 and ROR response element (RORE) to repress core circadian clock genes^,. When REV-ERBα is not expressed, the nuclear receptor RAR-related orphan receptor (ROR) binds these motifs instead and recruits nuclear receptor co-activator 2 (NCoA2) and histone acetyltransferases (HATs) to activate gene transcription. In the depiction, ZT 0–12 is the light period and ZT 12–24 is the dark period. b | REV-ERBα tethered to hepatocyte nuclear factor 6 (HNF6) recruits HDAC3 through binding to the NCoR complex to mediate circadian repression of metabolic genes. In the absence of REV-ERBα during the dark period, the HATs p300, CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF; also known as KAT2B) acetylate nearby histones and promote metabolic gene expression. c | Prospero homeobox protein 1 (PROX1) forms a distinct co-repressor module at enhancers bound by HNF4α independently of REV-ERBα. PROX1 and HDAC3 are co-recruited to HNF4α-bound enhancers enriched with different C/EBP transcription factors. Ac, acetyl group; GPS2, G protein pathway suppressor 2; H3K27ac, acetylated histone H3 lysine 27; H3K9ac, acetylated histone H3 Lysine 9; TBL1X, transducin β-Like 1, X-Linked; TBL1XR1, TBL1-reLated protein 1; TF, transcription factor.

Fig. 3 |. HDAC3 primes thermogenic gene transcription in brown adipose tissue.

a | In brown adipose tissue (BAT), histone deacetylase 3 (HDAC3) primes the expression of Ucp1 (which encodes mitochondrial brown fat uncoupling protein 1), tricarboxylic acid (TCA) cycle genes, oxidative phosphorylation genes and oxidative metabolism genes to facilitate rapid UCP1-dependent thermogenesis upon exposure to acute cold. b | A genomic view of the Ucp1 locus is shown, highlighting the co-activator activity of HDAC3 at oestrogen-related receptor-α (ERRα)-bound enhancers in BAT. Global run-on sequencing (GRO-seq) data demonstrate strong enhancer RNA (eRNA) transcription at Ucp1 enhancers and transcription of the Ucp1 gene in control BAT. Upon loss of HDAC3, eRNA transcription and expression of the Ucp1 gene are lost at enhancers bound by HDAC3, ERRα and peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) (another ERRα co-activator). The GRO-seq y axis represents reads per kilobase per million; the chromatin immunoprecipitation followed by sequencing (ChlP-seq) y axis represents reads per million. c | In BAT, HDAC3 activates PGC1α by deacetyLating it^,,. HDAC3 and ERRα bind to enhancers of the Ppargcla and Ppargclb genes to promote their basal transcription levels. Increased expression of PGC1α facilitates an autoreguLatory loop maintained by HDAC3, ERRα and PGC1α, which drives the transcription of Ucp1 and oxidative phosphorylation genes to ensure thermogenic aptitude and survival upon exposure to a cold environment. Notably, enhancers bound by HDAC3, ERRα and PGC1α are also marked by the brown fat lineage factor early B cell factor 2 (EBF2)^,. CBP, CREB-binding protein; ERRE, ERR response element; GPS2, G protein pathway suppressor 2; H3K27ac, acetylated histone H3 Lysine 27; H3K9ac, acetylated histone H3 Lysine 9; NCoA1, nuclear receptor co-activator l; NCoR, nuclear receptor co-repressor l; SMRT, silencing mediator of retinoic acid and thyroid hormone receptor; TBL1X, transducin β-Like l, X-Linked; TBL1XRl, TBL1-reLated protein l; TSS, transcription start site.

Fig. 4 |. HDAC3 influences cardiac development through deacetylase-independent mechanisms.

a | Histone deacetylase 3 (HDAC3) prevents the precocious differentiation of cardiac progenitor cells and premature expression of cardiomyocyte genes^–. HDAC3 tethers cardiac lineage genes located in lamina-associated domains (LADs) to the nuclear periphery for silencing. HDAC3 bound to the nuclear receptor co-repressor 1 (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complexes on chromatin interacts with the lamina proteins zinc-finger and BTB domain-containing protein 7B (ZBTB7B) and lamina-associated polypeptide 2, isoform-β (LAP2β) to tether LADs to the nuclear lamina, where they become facultative heterochromatin and enriched in the repressive histone H3 lysine 9 dimethylation (H3K9me2) modification^–. The release of LADs from the nuclear periphery alters their chromatin configuration and facilitates the expression of cardiomyocyte genes^,. b | In the second heart field (SHF), the non-enzymatic activity of HDAC3 represses transforming growth factor-β (TGFβ) signalling by recruiting the H3K27 methyltransferase Polycomb repressive complex 2 (PRC2) to the Tgfb1 gene. EED, embryonic ectoderm development protein; EZH2, enhancer of zeste homologue 2; GPS2, G protein pathway suppressor 2; H3K27me3, histone H3 lysine 27 trimethylation; NR, nuclear receptor; TF, transcription factor; SUZ12, suppressor of zeste 12 protein homologue; TBL1X, transducin β-like 1, X-linked; TBL1XR1, TBL1-related protein 1.

Fig. 5 |. HDAC3 controls brain development, glial cell fate and the formation of long-term memory.

a | Histone deacetylase 3 (HDAC3) controls brain development through maintenance of T-box brain 1 (Tbr1) gene expression or preservation of the Tbr1⁺ progenitor cell population. Loss of HDAC3 leads to impaired differentiation and migration of neural progenitor cells (NPCs), resulting in severe brain cytoarchitectural defects. b | HDAC3 controls glial cell fate. HDAC3 inhibits intermediate primitive oligodendrocyte progenitor cells (OPCs) and OPCs from undergoing astrogliogenesis, thereby promoting the formation of oligodendrocytes. HDAC3 inhibition of astroglial differentiation occurs through deacetylation and inhibition of signal transducer and activator of transcription 3 (STAT3), and by interaction with the histone acetyltransferase p300 to activate oligodendrocyte gene enhancers^,. Loss of HDAC3 decreases oligodendrocyte numbers and increases astrocyte numbers^,. c | In the hippocampus, HDAC3 represses nuclear receptor subfamily 4, group A, member 2 (Nr4a2) gene, which is important for the formation of long-term memory and object recognition. HDAC3 also regulates the Nr4a2 gene in the nucleus accumbens, where HDAC3 binding at enhancers is attenuated by cocaine use, which may facilitate long-term memories associated with drug abuse and reinforce future use. d | HDAC3 is recruited to specific sites of methylated DNA by the nuclear receptor co-repressor 1 (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complexes through their interaction with methyl-CpG-binding protein 2 (MECP2), which is implicated in Rett syndrome^,. There, HDAC3 deacetylates and activates the transcription factor forkhead box protein O3 (FOXO3) to promote neuronal gene expression. Ac, acetyl group; GPS2, G protein pathway suppressor 2; H3K27ac, acetylated histone H3 lysine 27; H3K9ac, acetylated histone H3 lysine 9; NR, nuclear receptor; TBL1X, transducin β-like 1, X-linked; TBL1XR1, TBL1-related protein 1; TF, transcription factor.

Fig. 6 |. HDAC3 regulates lung development, intestinal homeostasis, pancreatic β-cell insulin secretion and skeletal muscle metabolism.

a | Histone deacetylase 3 (HDAC3) regulates the differentiation of lung epithelial cells through repression of the Dlk1-Dio3 and miR-17–92 microRNA (miRNA) clusters. Increased expression of miRNAs represses genes in the transforming growth factor-β (TGFβ) signalling pathway, leading to defective extracellular matrix formation and failure of alveolar cell spreading. Defects in cell spreading and flattening impair lung sacculation and aίveoίogenesis. b | In intestinal epithelial cells (IECs), HDAC3 is required for maintenance of the epithelial barrier that separates the gut lumen from the systemic circulation, ensures Paneth cell survival, controls cell proliferation and protects against enteric bacteria. HDAC3 in IECs prevents enteric infection by signalling to intraepithelial CD8⁺ T lymphocytes (IELs) to mount a protective interferon-γ (IFNγ) immune response. c | Late in the day, at pre-dusk hours (Zeitgeber time (ZT) 10–12), HDAC3 and REV-ERBα repress branched-chain amino acid (BCAA) catabolism and the purine nucleotide cycle (PNC) pathway through repression of branched-chain amino acid aminotransferase, mitochondrial (BCAT2) and AMP deaminase 3 (AMPD3), respectively, to promote glucose utilization during the upcoming feeding cycle when glucose supply is abundant. At pre-dawn hours (ZT 22–24), when REV-ERBα and HDAC3 do not bind, increased BCAT2 and AMPD3 expression promotes the utilization of protein and lipid fuels over glucose to supply metabolic intermediates to the tricarboxylic acid (TCA) cycle. Muscle utilization of protein and lipid fuels during periods of daily fasting preserves glucose supplies for the brain and other vital organs. Ac, acetyl group; GPS2, G protein pathway suppressor 2; IL-18, interίeukin-18; NCoR, nuclear receptor co-repressor 1; NR, nuclear receptor; RORE, ROR response element; SMRT, silencing mediator of retinoic acid and thyroid hormone receptor; TBL1X, transducin β-like 1, X-linked; TBL1XR1, TBL1-reίated protein 1; TF, transcription factor.

Fig. 7 |. HDAC3 regulates distinct mouse tissue-specific gene expression programmes.

A heat map illustrating the differential gene expression and hierarchical clustering of ten mouse tissues is shown, which characterize tissue-specific histone deacetylase 3 (HDAC3)-dependent gene expression programmes achieved through the numerous and complex tissue-specific regulatory mechanisms highlighted in this Review. We display all the expressed genes in each tissue as log2 of the fold change (FC) of HDAC3 knockout versus controls (false discovery rate <0.05); the rows (tissues) were sorted by hierarchical clustering. Gene expression data were obtained from publicly available Gene Expression Omnibus (GEO) data sets, normalized for cross-platform comparisons and log-transformed; comparisons were made using the R package limma. The GEO data sets used for this analysis are GSE98650, GSE90531, GSE83927, GSE72917, GSE50188, GSE85929, GSE33609, GSE79696 and GSE68991. IEC, intestinal epithelial cell; FOXP3, forkhead box protein P3; TCRβ, T cell receptor-β; T_reg cell, regulatory T cell.