The many roles of histone deacetylases in development and physiology: implications for disease and therapy

Abstract

Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice have revealed highly specific functions of individual HDACs in development and disease. Mutant mice lacking individual HDACs are a powerful tool for defining the functions of HDACs in vivo and the molecular targets of HDAC inhibitors in disease.

Figure 1. The histone deacetylase (HDAC) superfamily, showing protein domains, loss-of-function phenotypes in mice and time point of lethality of the knockouts

Green rectangles indicate the conserved HDAC domain; numbers following the HDAC domain indicate the number of amino acids. Myocyte enhancer factor 2 (MEF2)-binding sites are marked by a blue square, and binding sites for the 14-3-3 chaperone protein are also shown. E, embryonic day; ND, not determined; P, days postnatal; S, serine phosphorylation sites; ZnF, zinc finger.

Figure 2. Control of heart development by histone deacetylase 1 (HDAC1) and HDAC2

a | Histological sections of hearts from wild type and HDAC2 knockout (KO) mice at postnatal day 1 (P1). Note the excessive number of cardiomyocytes in the mutant heart, which fill the chambers of the left ventricle (lv) and right ventricle (rv). b | Schematic of the role of HDAC2 in the repression of cardiomyocyte proliferation through inhibition of homeodomain-only protein (HOP). c | Histological sections of hearts from wild-type mice and mice with a cardiac deletion of HDAC1 and 2 at P11. Note the dilatation of the right ventricle in the mutant, which is indicative of heart failure. d | Schematic of the redundant roles of HDAC1 and 2 in regulation of calcium channel and skeletal muscle genes in cardiomyocytes via repression of neuron-restrictive silencer factor (NRSF) and other transcription factors. Parts a and c are reproduced, with permission, from REF. © (2007) Cold Spring Harbor Laboratory Press.

Figure 3. Control of chondrocyte hypertrophy by histone deacetylase 4 (HDAC4)

a | Ribs from neonatal mice stained for bone (red) and cartilage (blue). Deletion of HDAC4 results in ossification of cartilage by the arrowhead), whereas overexpression of HDAC4 in the cartilage of transgenic mice prevents ossification. b | Schematic of the repressive influence of HDAC4 on myocyte enhancer factor 2 (MEF2) and runt related transcription factor 2 (RUNX2) in the pathway for chondrocyte proliferation and hypertrophy. IHH, Indian hedgehog; KO, knockout; PTHrP, parathyroid hormone-related peptide. Part a is reproduced, with permission, from REF. © (2007) Cell Press.

Figure 4. Control of pathological cardiac hypertrophy by class IIa histone deacetylases (HDACs)

a | Histological sections of hearts from wild-type and HDAC9 knockout (KO) adult mice. Mice were subjected to cardiac stress by expression of a cardiac-specific transgene encoding activated calcineurin, which drives pathological hypertrophy. Note that HDAC9 knockout mice have normal hearts in the absence of stress, but display cardiomegaly in response to stress, owing to loss of the growth-inhibitory function of HDAC9. b | Schematic of the repressive influence of class IIa HDACs on myocyte enhancer factor 2 (MEF2) and pathological cardiac remodelling. Stress-inducible kinases, such as calcium/calmodulin-dependent protein kinase (CaMK) and protein kinase D (PKD), induce the phosphorylation of class IIa HDACs, which creates docking sites for the 14-3-3 chaperone protein, resulting in nuclear export with consequent activation of MEF2 and its downstream target genes, which are involved in cardiac remodelling. Part a is reproduced, with permission, from REF. (2007) © Cell Press.

Figure 5. Control of slow myofibre gene expression by class IIa histone deacetylases (HDACs)

a | Histological sections of soleus muscle from wild-type and HDAC5;9 double mutant knockout (KO) mice stained for type I myosin heavy chain, a marker of type I slow myofibres. Note the increase in slow myofibres after deletion of class IIa HDACs. b | Schematic of the repressive influence of class IIa HDACs on myocyte enhancer factor 2 (MEF2), which acts together with PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) and NFAT (nuclear factor of activated T-cells) to promote the formation of slow myofibres. Signalling by calcium/calmodulin-dependent protein kinase (CaMK) and protein kinase D (PKD) induces the phosphorylation of class IIa HDACs, which creates docking sites for the 14-3-3 chaperone protein, resulting in nuclear export with consequent activation of slow myofibre genes. c | A MEF2-dependent negative feedback loop for the control of HDAC9 expression during muscle differentiation. Myogenic basic helix-loop-helix (bHLH) transcription factors activate the expression of MEF2, which then amplifies and sustains the expression of myogenic bHLH genes. Myogenic bHLH factors and MEF2 also cooperate to activate skeletal muscle differentiation genes. In addition, MEF2 activates the expression of HDAC9, which in turn represses MEF2 activity. Signals that influence myogenesis activate HDAC kinases and thereby repress HDAC9 activity, providing a ‘rheostat’ mechanism for the control of myogenesis. Part a is reproduced from REF. .

Figure 6. Control of endothelial integrity by histone deacetylase 7 (HDAC7)

a | Wild-type and HDAC7 knockout (KO) embryos at embryonic day 10.5 (E10.5). The absence of HDAC7 results in vascular rupture, pericardial oedema and haemorrhaging throughout the mutant embryos. b | Schematic of the role of HDAC7 in maintenance of vascular integrity. HDAC7 is expressed specifically in endothelial cells, where it represses the activity of myocyte enhancer factor 2 (MEF2). In the absence of HDAC7, MEF2 activity is elevated, resulting in upregulation of matrix metalloproteinase 10 (MMP10) and degradation of cell–cell interactions required for vascular integrity. Deletion of HDAC7 also leads to downregulation of tissue inhibitor of metalloproteinase 1 (TIMP1), presumably through indirect mechanisms, which further enhances MMP10 activity. Part a is reproduced, with permission, from REF. © (2007) Cell Press.