Class IIa HDACs – new insights into their functions in physiology and pathology Maribel Parra Cellular Differentiation Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Spain
Keywords cell differentiation; class IIa HDACs; development; HDAC4; HDAC5; HDAC7; HDAC9; immune system; metabolism; neuronal physiology and pathology; transcriptional repression Correspondence M. Parra, Cellular Differentiation Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Avenida Gran Via 199, 08908 L’Hospitalet, Barcelona, Spain Fax: +34 932 607219 Tel: +34 932 607133 E-mail: [email protected]
HDAC4, 5, 7 and 9 constitute the class IIa histone deacetylases (HDACs) within the large family of protein deacetylases. Class IIa HDACs have unique features that distinguish them from other HDACs. They contain an N-terminal domain that is required for their interaction with tissue-specific transcription factors and recruitment to their target genes. The N-terminal domain on class IIa HDACs also bears conserved serine residues that undergo signal-dependent phosphorylation, which brings about nuclear export of the enzymes and de-repression of their targets. One of the most important aspects of class IIa HDACs is their expression in specific tissues and organs within the organism, where they have crucial roles in development and differentiation processes. This review brings up to date our knowledge of the physiological and pathological functions of class IIa HDACs, focusing in particular on the most recent discoveries from in vivo studies of mouse model systems.
(Received 11 July 2014, revised 13 September 2014, accepted 18 September 2014) doi:10.1111/febs.13061
Introduction Histone or protein deacetylases (HDACs) are enzymes with a crucial role in many diverse physiological and pathological processes. HDAC4, 5, 7 and 9 constitute the class IIa HDAC subtype within the large family of HDACs. Since their discovery, significant progress has been made towards understanding their biological functions and the mechanisms governing their activity. Researchers in the field have addressed how class IIa HDACs interact with tissue-specific transcription fac-
tors, and their signaling-dependent nucleocytoplasmic shuttling effect on the repression/de-repression of their target genes in specific cell types. Phenotypic analysis of class IIa HDAC knockout and transgenic mouse models has confirmed their crucial role in important developmental and differentiation systems [1–4]. The present review summarizes the most recent evidence for the role of class IIa HDACs as essential regulators in specific physiological and pathological systems.
Abbreviations AMPK, cAMP response element binding protein; ATM, ataxia-telangiectasia mutated; BDMR syndrome, brachydactyly mental retardation syndrome; CREB, cAMP response element binding protein; FOXO, Forkhead box class O; G6Pase, glucose-6-phosphatase; HDAC, histone deacetylase; MEF2, myocyte enhancer factor 2; PKC, protein kinase C; PKCu, protein kinase C mu; SIK3, salt-inducible kinase 3; SMRT/NCoR, silencing mediator for retinoid and thyroid receptors/nuclear receptor corepressor; Treg cell, regulatory T cell.
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shown to contain interacting binding sites for members of the myocyte enhancer factor 2 (MEF2) family of transcription factors [12,15–18]. However, other transcription factors have also been reported to be class IIa HDAC partners, such as Runx2, calmodulinbinding transcription activator and serum response factor, among others [1–4]. A second peculiarity shared by HDAC4, 5, 7 and 9 is that their N-terminal domain has highly conserved serine residues that undergo signal-dependent phosphorylation (Fig. 1). Under basal conditions, class IIa HDACs are unphosphorylated and located in the nucleus, where they are recruited to their target genes through interaction with transcription factors, enabling their transcriptional repressive function. However, class IIa HDACs become phosphorylated in response to specific signals, leading to disruption of the interaction with transcription factors, their export to the cytoplasmic compartment, and de-repression of their targets. Previous reviews have provided detailed descriptions of the extracellular signals and kinases involved in the phosphorylation of class IIa HDACs [1–3]. A third intriguing feature of class IIa HDACs is their lack of measurable enzymatic activity. Although they have a highly conserved catalytic domain, they exhibit minimal deacetylase activity on acetylated histones. To date, no histone or other protein substrates have been identified for class IIa HDACs. In fact, it has been shown that their enzymatic activity depends on their recruitment into a multiprotein complex containing HDAC3 and silencing mediator for retinoid and thyroid receptors/nuclear receptor corepressor [19]. It has been proposed that class IIa HDACs may not be real enzymes, and that they act as adaptors of repressor complexes. Finally, class IIa HDACs appear to be expressed in a tissue-specific manner, and have been shown to exert their transcriptional repressive function in skeletal, cardiac and smooth muscle, bone, the immune system, the vascular system and the brain, among others. Therefore, class IIa HDACs are currently to be considered crucial regulators of specific developmental and differentiation processes. However,
Histone deacetylation and HDACs: a brief overview Fifty years ago, Allfrey et al. made the seminal discovery that acetylation of histones was associated with the regulation of gene expression [5]. Acetylation neutralizes the positive charge of the histone lysine residues, producing a relaxed chromatin conformation that allows access of the transcription machinery [2]. In contrast, histone deacetylation induces a condensed chromatin state that is associated with the repression of gene transcription [2]. There is much evidence to suggest that lysine acetylation and deacetylation also occur in a large number of non-histone proteins, such as transcription factors and cytoplasmic proteins, and affect not only gene transcription but also other cellular processes [6]. Two types of antagonistic enzymes control the reversibility of lysine acetylation: histone or protein acetylases and histone or protein deacetylases (HDACs) [7]. HDACs are key transcriptional repressors in many diverse physiological and pathological processes. So far, 18 human HDACs have been identified and grouped into four classes. Class I HDACs (HDAC1, 2, 3 and 8) share a high degree of homology with the yeast transcriptional regulator RPD3, class II HDACs are closely related to HDA1 (HDAC4, 5, 6, 7, 9 and 10), class III HDACs, also named sirtuins, are homologous with Sir2 (SIRT1, 2, 3, 4, 5, 6 and 7), and the most recently classified class IV HDAC (HDAC11) is homologous with class I and II enzymes. Class II HDACs are further sub-divided into class IIa forms (HDAC4, 5, 7 and 9) and class IIb forms (HDAC6 and 10) [1,2].
Class IIa HDACs Class IIa HDACs were discovered and cloned by several laboratories in the early 2000s [8–15]. The first surprising feature that justifies their classification within their own sub-family, differentiating them from class I HDACs, is the presence of a long N-terminal domain in addition to their C-terminal catalytic domain (Fig. 1). The N-terminal domain was first
Adaptor and phosphorylation domain
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Fig. 1. Scheme of class IIa HDAC domains.
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most of the studies demonstrating their tissue specificity have employed in vitro experimental approaches, using culture cells. Seminal work from the laboratory of Eric Olson, a pioneer scientist in the field of class IIa HDAC research, has contributed to our understanding of the functions of class IIa HDACs, confirming their role in development and differentiation. Between 2004 and 2006, Olson and his colleagues reported the generation and phenotypic characterization of knockout mice for each class IIa HDAC family member. They reported that mice deficient in HDAC4 display a failure of osteogenesis resulting from premature bone calcification [20]. Mice lacking HDAC5 and/or HDAC9 exhibit exacerbated cardiac hypertrophy in response to stress induced by artificially induced aortic stenosis [21,22]. In addition, mice deficient in HDAC7 show embryonic lethality at day 11, resulting from a failure to form tight junctions in the developing circulatory system [23] (Table 1). Since these initial studies, other researchers in the field have used class IIa HDAC mouse models to investigate further their role as transcriptional repressors in physiology and pathology (Table 1). Their most recent findings are summarized below.
Neuronal physiology and pathology Increasing evidence indicates a crucial role for HDAC4 in physiological and pathological neuronal development and function. In addition to being expressed in muscle and bone, HDAC4 is found at high levels in neurons, where it is mainly located in the cytoplasmic compartment. As mentioned above, mice deficient in HDAC4 show severe skeletal abnormalities and die within 2 weeks of birth. The brains of these mice are 40% smaller than those of their littermate controls. In particular, HDAC4 knockout mice show neuronal developmental defects, such as a smaller cerebellum [24]. Two recent reports have identified an important role for HDAC4 in neuronal synaptic plasticity and memory formation. Kim et al. showed that specific deletion of HDAC4 in the forebrain of mice resulted in the impairment of memory, behavioral learning and long-term synaptic plasticity [25]. Simultaneously, Sando et al. shed light on the mechanisms involved in HDAC4-mediated regulation of synaptic plasticity and memory. They found that, when present in the nucleus, HDAC4 governs the gene transcriptional program characteristic of the central synapsis, affecting information processing in the brain [26]. Interestingly,
Table 1. Phenotypic summary of class IIa HDACs mouse models. Class IIa HDACs mouse model HDAC4 Knockout Conditional knockout in the forebrain Transgenic mice: HDAC4 catalytic mutant in the forebrain HDAC4 knockout in a mouse model of Huntington disease HDAC5 Knockout Knockout Knockout HDAC4 knockout in a mouse model of Alzheimer disease HDAC7 Knockout Conditional knockout in the thymus Transgenic mice: HDAC7 phosphorylation mutant in the thymus HDAC9 Knockout Knockout Knockout HDAC9 knockout in a mouse model of autoimmunity Knockout
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Chondrocyte differentiation defect. Premature bone ossification Small cerebellum, Purkinje cell degeneration Impairment of memory, behavioral learning and long-term synaptic plasticity Defect in spatial learning and memory
20, 24
Delay in the formation of aggregates and rescue of neuronal synaptic function
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Exacerbated cardiac hypertrophy after stress Decreased axon regeneration after injury Increased sensitivity to cocaine chronic exposure Impairment of memory function
21 33 34 36
Failure to form tight junctions in the developing circulatory system Impairment of positive selection of single-positive (SP) CD4 lymphocytes Block of the negative selection of thymocytes and lethal autoimmune disease
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Exacerbated cardiac hypertrophy after stress Increased number of Treg cells Increased resistant to induced colitis Decreased cell proliferation, inflammation, autoantibody production and increased survival of mice Improvement of adipogenic differentiation and systemic metabolic state during an Hight fat diet
22 47 46 48
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transgenic mice expressing a truncated catalytic domain form of HDAC4 specifically in the forebrain showed a defect in spatial learning and memory [26]. These reports suggest that HDAC4 may be deleted or mutated in human syndromes involving mental retardation. Further reports have described that the HDAC4 locus is in fact deleted or mutated in patients with brachydactyly mental retardation (BDMR) syndrome, which is characterized by intellectual disabilities, developmental delays, behavioral abnormalities and skeletal abnormalities. BDMR syndrome is associated with a deletion in chromosome 2q37 involving the HDAC4 gene [27]. Other clinical cases that do not involve this specific deletion present de novo mutations in HDAC4 [27]. Other reported analyses of cases of familial BDMR syndrome have confirmed the association of HDAC4 mutation or deletion with the pathogenesis of the disease [28]. One of the clinical studies found that HDAC4 was expressed in a mother with mild symptoms of BDMR syndrome, while her son presented a more severe phenotype and lower levels of HDAC4. It is of note that the levels of HDAC4 mRNA were correlated with the severity of the disease, indicating that the phenotype of BDMR syndrome is modulated by HDAC4 in a dose-dependent manner [28]. In a second clinical study, Villavicencio-Lorini et al. investigated a three-generation familial case of BDMR syndrome with microdeletion of chromosome 2q37.3 involving the HDAC4 gene, in which HDAC4 haploinsufficiency was found to be responsible for the patients’ psychomotor and behavioral abnormalities [29]. HDAC4 is also known to be involved in ataxia telangiectasia neurodegenerative disease. It is expressed in the cytoplasm of normal, but is found in the nucleus of Purkinje cells in ataxia telangiectasia patient samples and ataxia-telangiectasia mutated-deficient mice. HDAC4 interacts with the transcription factors MEF2A and cAMP response element binding protein, resulting in an altered gene expression program associated with degeneration [30]. Finally, HDAC4 has also been associated with the pathogenesis of Huntington’s disease. Mielcarek et al. reported that HDAC4 associates with huntingtin and co-localizes with cytoplasmic inclusions [31]. Strikingly, HDAC4 reduction delayed the formation of aggregates in the cytoplasm and rescued neuronal synaptic function in Huntington’s disease mouse models. This correlates with an improvement in motor coordination and increased lifespan [31]. Studies in the laboratory of Valeria Cavalli have indicated the involvement of HDAC5 in axon regeneration, which is essential for rebuilding functional conFEBS Journal 282 (2015) 1736–1744 ª 2014 FEBS
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nections between injured neurons and their targets. Cho and Cavalli showed that axon injury led to tubulin deacetylation, an event that is necessary for axon regeneration and that requires Protein kinase C-mediated activation of HDAC5 [32]. An elegant study performed in the same laboratory subsequently demonstrated that HDAC5 plays a role in axonal regeneration. Axotomy, a type of axon injury, in cultured dorsal root ganglion neurons induces the nuclear export of HDAC5 in a calcium- and Protein kinase C mu-dependent manner, leading to increased histone acetylation and activation of a pro-regenerative gene transcription program [33]. The cytoplasmic accumulation of HDAC5 is necessary for axon regeneration as expression of an HDAC5 phosphorylation mutant that is always located in the nuclear compartment interferes with axon regeneration [33]. HDAC5 has also been linked to the behavioral response to cocaine. Histone acetylation is altered in animal models of drug addiction. After chronic exposure to cocaine in mice, HDAC5 becomes phosphorylated and shows decreased activity in the nucleus accumbens, a major brain reward region. Strikingly, HDAC5-deficient mice are more sensitive than wild-type controls to the chronic effects of cocaine [34]. More recently, Taniguchi et al. shed light on the molecular mechanisms by which cocaine modulates HDAC5 function. They found that cAMP signaling leads to dephosphorylation and transient nuclear accumulation of HDAC5 in the nucleus accumbens, suppressing the development of cocaine reward behavior in vivo [35]. HDAC5 has also been reported to play a role in Alzheimer’s disease: HDAC5 deficiency in a mouse model for Alzheimer’s disease impairs memory function [36]. Recently, HDAC9 has also been linked to neuronal physiology and pathology. Sugo et al. reported that HDAC9 is expressed in the mouse cerebellar cortex during postnatal cortical development [37]. After spontaneous neuronal activity, HDAC9 is exported to the cytoplasm in postnatal cortical neurons, leading to expression of the gene c-Fos and promoting dendritic growth [37]. Whether neuronal development is compromised in HDAC9-deficient mice remains to be established. In the context of neuronal pathology, HDAC9 has been associated with schizophrenia. Lang et al. recently reported that HDAC9 is hemizygously deleted in patients with schizophrenia [38]. Strikingly, the authors observed that HDAC9 is widely expressed in areas of the mouse brain associated with the neuropathology of schizophrenia, and the expression is exclusively detected in post-mitotic neurons, indicating that HDAC9 may be crucial to the correct function of mature neurons [38].
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Taken together, these studies indicate that HDAC4, HDAC5 and HDAC9 may be promising therapeutic targets in diverse human neurological disorders and diseases.
The immune system Studies from the laboratory of Eric Verdin indicated that, among the various class IIa HDACs, HDAC7 was highly expressed in developing thymocytes at the CD4+ CD8+ double-positive stage [12]. Under basal conditions, HDAC7 localizes to the nucleus of thymocytes, where it exerts transcriptional repressive functions [12,39]. In this context, HDAC7 was found to repress the transcription of the orphan nuclear receptor Nur77, leading to the inhibition of apoptosis or negative selection of T cells [12]. After T-cell receptor activation, HDAC7 becomes phosphorylated at conserved serine residues located in its N-terminal region and is exported to the cytoplasm, resulting in derepression of Nur77 and induction of apoptosis [40]. HDAC7 was subsequently reported to be involved not only in repression of Nur77, but also in the transcriptional regulation of a large number of genes involved in both positive and negative selection of thymocytes [39]. More recently, Kasler et al. presented definitive evidence for the role of HDAC7 in T-cell development. First, using a conditional knockout mouse model, they demonstrated that specific deletion of HDAC7 in double-positive thymocytes results in a significant reduction in survival or positive selection of single-positive CD4+ lymphocytes [41]. Microarray analysis showed that HDAC7 deficiency in thymocytes leads to the de-regulation of the genetic program characteristic of CD4+ single-positive T cells. Second, a transgenic mouse model expressing an HDAC7 phosphorylation mutation that cannot be exported to the cytoplasm in thymocytes revealed the relevance of the signal-dependent repressive function of HDAC7. These mice showed a profound block of the negative selection of thymocytes, leading to escape of autoreactive T cells to the periphery, and a lethal autoimmune disease in the exocrine pancreas and other organs [42]. Gene expression profiling showed that the HDAC7 phosphorylation mutation suppressed the gene expression program characteristic of negative selection of thymocytes. In a recent paper, Liu et al. established a link between HDAC7 and autoimmune disease in humans. The authors identified novel risk and susceptibility loci for primary sclerosing cholangitis, a severe autoimmune disease of the liver. Interestingly, one of the risk loci associated with the disease comprised the HDAC7 gene, indicating its role in primary sclerosing cholangitis etiology [43]. Whether 1740
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HDAC7 is involved in other human autoimmune diseases remains to be established. The relevance of HDAC7 in T-cell biology has recently been confirmed. Using a quantitative proteomic approach to identify the phosphoproteome of cytotoxic T cells, Navarro et al. showed that HDAC7 is constitutively phosphorylated and localized in the cytoplasm of this type of lymphocyte [44]. This is crucial for the proper function of cytotoxic T cells, as expression of a phosphorylation-deficient mutant of HDAC7 that is always localized in the nucleus interfered with the proliferation capacity of cytotoxic T cells [44]. It has recently been reported that, in addition to its expression in thymocytes, HDAC7 is found at high levels in B lymphocytes but is not present in myeloid cells such as macrophages [45]. Using an immune cellular reprogramming system, we found that HDAC7 is down-regulated during the conversion of pre-B cells into macrophages [45]. Exogenous expression of HDAC7 in this system interfered with the acquisition of essential macrophage-specific cell functions. Moreover, gene expression analysis demonstrates that reexpression of HDAC7 interferes with the establishment of the myeloid gene transcriptional program [45]. From a mechanistic point of view, we reported that HDAC7 interacts with the transcription factor MEF2C and is recruited to the promoter of macrophage genes in Bcell precursors. siRNA-mediated knockdown of HDAC7 leads to the de-repression of myeloid genes in B lymphocytes, indicating that HDAC7 may be an essential transcriptional repressor of lineage-inappropriate genes in B cells. A role for HDAC7 in B-cell development in in vivo mouse models remains to be established. Together, the recent reports suggest that HDAC7 is a lymphoid-specific transcriptional repressor that is involved in regulating several crucial aspects of B- and T-cell biology and development. Over the last few years, HDAC9 has also emerged as a crucial transcriptional repressor in the immune system. It is highly expressed in regulatory T cells (Treg cells), which are an important subset of T lymphocytes that limit immune responses and are critical for maintaining immune self-tolerance. Treg lymphocytes are characterized by expression of the transcription factor FOXP3 that mediates gene activation and repression. HDAC9 is highly expressed in human Treg cells and interacts with FOXP3 [46]. In the mouse, HDAC9 was also found to be specifically expressed in Treg cells and localized in the nucleus of resting cells, but was exported to the cytoplasm after T-cell receptor activation. Definitive proof that HDAC9 controls Treg function was obtained from a knockout mouse model. HDAC9-deficient mice had 50% more FOXP3-positive FEBS Journal 282 (2015) 1736–1744 ª 2014 FEBS
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cells than wild-type mice, and Treg cells lacking HDAC9 were found to be more suppressive than the control cells [47]. The authors also reported a function of HDAC9 in inflammatory bowel diseases such as colitis, in which Treg cells are known to play a crucial role. HDAC9-deficient mice were resistant to colitis induced by dextran sulfate sodium [47]. More recently, using colitis mouse models, de Zoeten et al. reported that Treg cells deficient in HDAC9 exhibit stronger repressive functions due to their greater ability to survive and proliferate [46]. HDAC9 functions have also been found to be associated with systemic autoimmunity. Yan et al. recently discovered that HDAC9 is highly expressed in various subsets of CD4+ T cells in autoimmune Murphy-Roths Lymphoma/Lymphoproliferative (MRL/lpr) mice as well as in CD4+ T cells of lupus patients [48]. Interestingly, HDAC9 deficiency in MRL/lpr mice gave rise to decreased cell proliferation, inflammation, auto-antibody production and increased survival of mice [48].
Energy metabolism and obesity Recently, two elegant studies have established a link between class IIa HDACs and energy/glucose metabolism. Mihaylova et al. reported that HDAC4, 5 and 7 are expressed in the liver, where they are phosphorylated by activated protein kinase family kinases and located in the cytoplasm [49]. However, in response to glucagon, a fasting hormone, they become dephosphorylated and translocate into the nucleus, where they are recruited to the promoters of gluconeogenic enzymes such as glucose-6-phosphatase-a. From a mechanistic point of view, HDAC4 and HDAC5 interact with the class I HDAC HDAC3, leading to the deacetylation and activation of Forkhead box class O (FOXO) family transcription factors and expression of their target genes. Knockdown of class IIa HDACs in murine liver cells results in inhibition of FOXO target genes, lowers blood glucose levels, and increases glycogen storage. Finally, class IIa HDAC knockdown in mouse models of type 2 diabetes ameliorates hyperglycemia, suggesting that inhibitors of class I/II HDACs may be potential therapeutic agents for treating metabolic syndrome [49]. In a parallel study using Drosophila as a model system, Wang et al. found that, under feeding conditions, HDAC4 is phosphorylated by salt-inducible kinase 3 (SIK3) and located in the cytoplasm [50]. However, during fasting, SIK3 becomes inactivated, resulting in the dephosphorylation and nuclear translocation of HDAC4, and FOXO deacetylation. SIK3 mutant flies are starvation-sensitive, reflecting FOXO-dependent increases in lipolysis that deplete triglyceride stores. FEBS Journal 282 (2015) 1736–1744 ª 2014 FEBS
Reducing HDAC4 levels restores lipid accumulation [50]. Studies in class IIa HDAC-deficient mice are required to further elucidate their role in metabolic processes. Recent reports have linked HDAC9 function to adipogenesis. Differentiation of pre-adipocytes into mature and functional adipocytes is a fundamental mechanism in obesity. HDAC9 was reported to be down-regulated before adipogenic differentiation. HDAC9-deficient pre-adipocytes show accelerated adipogenic differentiation, indicating that HDAC9 may act as a negative regulator of adipogenesis [51]. Very recently, the same laboratory demonstrated a role for HDAC9 in obesity [52]. In response to chronic caloric excess, the differentiation of pre-adipocytes into functional adipocytes is compromised. After administration of a chronic high-fat diet in mice, HDAC9 deficiency was found to result in improvement of adipogenic differentiation and establishment of a systemic metabolic state [52]. In the absence of HDAC9, mice on a high-fat diet experience diminished weight gain, and have improved glucose tolerance and insulin sensitivity and reduced hepatosteatosis [52]. Taken together, these findings indicate that HDAC9 may be a promising therapeutic target for combating obesity-related metabolic diseases.
Concluding remarks The existence of 18 mammalian HDACs indicates that they may play highly specific roles in an organism under normal and pathological circumstances. Indeed, gene deletion for individual HDACs in mice has confirmed their highly specific biological functions. This is particularly evident for class IIa HDACs. Since their discovery 14 years ago, we have learnt that they are enzymes of considerable importance in development and differentiation. More recent studies indicate that they may be involved in human diseases or disorders that affect the tissues and organs in which they are expressed. Therefore, class IIa HDACs appear to be promising therapeutic targets. Human genetics approaches, including next-generation ultra-sequencing techniques, will enable us to measure class IIa HDAC expression levels as well as understand their patterns of mutation and deletion in human disease. Finally, given the specificity of each of these enzymes, the development of isoform-specific HDAC inhibitors or modulators is of central importance to discriminate between the types of HDACs and to target only the enzymes involved in a particular pathological situation. Responding to this challenge will shape future therapeutic approaches to patients with specific diseases.
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Acknowledgements This work was supported by grant SAF2011-28290 from the Spanish Ministry of Economy and Competitiveness (MINECO).
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Maribel Parra wrote the review.
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37 Sugo N, Oshiro H, Takemura M, Kobayashi T, Kohno Y, Uesaka N, Song WJ & Yamamoto N (2010) Nucleocytoplasmic translocation of HDAC9 regulates gene expression and dendritic growth in developing cortical neurons. Eur J Neurosci 31, 1521–1532. 38 Lang B, Alrahbeni TM, Clair DS, Blackwood DH, McCaig CD & Shen S & the International Schizophrenia Consortium (2012) HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells. Am J Stem Cells 1, 31–41. 39 Kasler HG & Verdin E (2007) Histone deacetylase 7 functions as a key regulator of genes involved in both positive and negative selection of thymocytes. Mol Cell Biol 27, 5184–5200. 40 Parra M, Kasler H, McKinsey TA, Olson EN & Verdin E (2005) Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. J Biol Chem 280, 13762–13770. 41 Kasler HG, Young BD, Mottet D, Lim HW, Collins AM, Olson EN & Verdin E (2011) Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/ CD8 double-positive thymocytes. J Immunol 186, 4782–4793. 42 Kasler HG, Lim HW, Mottet D, Collins AM, Lee IS & Verdin E (2012) Nuclear export of histone deacetylase 7 during thymic selection is required for immune selftolerance. EMBO J 31, 4453–4465. 43 Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, Andreassen OA, Weersma RK, Weism€ uller TJ, Eksteen B et al. (2013) Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 45, 670–675. 44 Navarro MN, Goebel J, Feijoo-Carnero C, Morrice N & Cantrell DA (2011) Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat Immunol 12, 352–361. 45 Barneda-Zahonero B, Roman-Gonzalez L, Collazo O, Rafati H, Islam AB, Bussmann LH, di Tullio A, De Andres L, Graf T, L opez-Bigas N et al. (2013) HDAC7 is a repressor of myeloid genes whose downregulation is required for transdifferentiation of pre-B cells into macrophages. PLoS Genet 9, e1003503. 46 de Zoeten EF, Wang L, Sai H, Dillmann WH & Hancock WW (2010) Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice. Gastroenterology 138, 583–594. 47 Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, Li B, Turka LA, Olson EN, Greene MI et al. (2007) Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13, 1299–1307.
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48 Yan K, Cao Q, Reilly CM, Young NL, Garcia BA & Mishra N (2011) Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J Biol Chem 286, 28833–28843. 49 Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez JG, Downes M, Evans RM, Montminy M & Shaw RJ (2011) Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145, 607–621. 50 Wang B, Moya N, Niessen S, Hoover H, Mihaylova MM, Shaw RJ, Yates JR, Fischer WH, Thomas JB & Montminy M (2011) A hormone-dependent
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module regulating energy balance. Cell 145, 596–606. 51 Chatterjee TK, Idelman G, Blanco V, Blomkalns AL, Piegore MG, Weintraub DS, Kumar S, Rajsheker S, Manka D, Rudich SM et al. (2011) Histone deacetylase 9 is a negative regulator of adipogenic differentiation. J Biol Chem 286, 27836–27847. 52 Chatterjee TK, Basford JE, Knoll E, Tong WS, Blanco V, Blomkalns AL, Rudich S, Lentsch AB, Hui DY & Weintraub NL (2014) HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding. Diabetes 63, 176–187.
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Keywords cell differentiation; class IIa HDACs; development; HDAC4; HDAC5; HDAC7; HDAC9; immune system; metabolism; neuronal physiology and pathology; transcriptional repression Correspondence M. Parra, Cellular Differentiation Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Avenida Gran Via 199, 08908 L’Hospitalet, Barcelona, Spain Fax: +34 932 607219 Tel: +34 932 607133 E-mail: [email protected]
HDAC4, 5, 7 and 9 constitute the class IIa histone deacetylases (HDACs) within the large family of protein deacetylases. Class IIa HDACs have unique features that distinguish them from other HDACs. They contain an N-terminal domain that is required for their interaction with tissue-specific transcription factors and recruitment to their target genes. The N-terminal domain on class IIa HDACs also bears conserved serine residues that undergo signal-dependent phosphorylation, which brings about nuclear export of the enzymes and de-repression of their targets. One of the most important aspects of class IIa HDACs is their expression in specific tissues and organs within the organism, where they have crucial roles in development and differentiation processes. This review brings up to date our knowledge of the physiological and pathological functions of class IIa HDACs, focusing in particular on the most recent discoveries from in vivo studies of mouse model systems.
(Received 11 July 2014, revised 13 September 2014, accepted 18 September 2014) doi:10.1111/febs.13061
Introduction Histone or protein deacetylases (HDACs) are enzymes with a crucial role in many diverse physiological and pathological processes. HDAC4, 5, 7 and 9 constitute the class IIa HDAC subtype within the large family of HDACs. Since their discovery, significant progress has been made towards understanding their biological functions and the mechanisms governing their activity. Researchers in the field have addressed how class IIa HDACs interact with tissue-specific transcription fac-
tors, and their signaling-dependent nucleocytoplasmic shuttling effect on the repression/de-repression of their target genes in specific cell types. Phenotypic analysis of class IIa HDAC knockout and transgenic mouse models has confirmed their crucial role in important developmental and differentiation systems [1–4]. The present review summarizes the most recent evidence for the role of class IIa HDACs as essential regulators in specific physiological and pathological systems.
Abbreviations AMPK, cAMP response element binding protein; ATM, ataxia-telangiectasia mutated; BDMR syndrome, brachydactyly mental retardation syndrome; CREB, cAMP response element binding protein; FOXO, Forkhead box class O; G6Pase, glucose-6-phosphatase; HDAC, histone deacetylase; MEF2, myocyte enhancer factor 2; PKC, protein kinase C; PKCu, protein kinase C mu; SIK3, salt-inducible kinase 3; SMRT/NCoR, silencing mediator for retinoid and thyroid receptors/nuclear receptor corepressor; Treg cell, regulatory T cell.
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shown to contain interacting binding sites for members of the myocyte enhancer factor 2 (MEF2) family of transcription factors [12,15–18]. However, other transcription factors have also been reported to be class IIa HDAC partners, such as Runx2, calmodulinbinding transcription activator and serum response factor, among others [1–4]. A second peculiarity shared by HDAC4, 5, 7 and 9 is that their N-terminal domain has highly conserved serine residues that undergo signal-dependent phosphorylation (Fig. 1). Under basal conditions, class IIa HDACs are unphosphorylated and located in the nucleus, where they are recruited to their target genes through interaction with transcription factors, enabling their transcriptional repressive function. However, class IIa HDACs become phosphorylated in response to specific signals, leading to disruption of the interaction with transcription factors, their export to the cytoplasmic compartment, and de-repression of their targets. Previous reviews have provided detailed descriptions of the extracellular signals and kinases involved in the phosphorylation of class IIa HDACs [1–3]. A third intriguing feature of class IIa HDACs is their lack of measurable enzymatic activity. Although they have a highly conserved catalytic domain, they exhibit minimal deacetylase activity on acetylated histones. To date, no histone or other protein substrates have been identified for class IIa HDACs. In fact, it has been shown that their enzymatic activity depends on their recruitment into a multiprotein complex containing HDAC3 and silencing mediator for retinoid and thyroid receptors/nuclear receptor corepressor [19]. It has been proposed that class IIa HDACs may not be real enzymes, and that they act as adaptors of repressor complexes. Finally, class IIa HDACs appear to be expressed in a tissue-specific manner, and have been shown to exert their transcriptional repressive function in skeletal, cardiac and smooth muscle, bone, the immune system, the vascular system and the brain, among others. Therefore, class IIa HDACs are currently to be considered crucial regulators of specific developmental and differentiation processes. However,
Histone deacetylation and HDACs: a brief overview Fifty years ago, Allfrey et al. made the seminal discovery that acetylation of histones was associated with the regulation of gene expression [5]. Acetylation neutralizes the positive charge of the histone lysine residues, producing a relaxed chromatin conformation that allows access of the transcription machinery [2]. In contrast, histone deacetylation induces a condensed chromatin state that is associated with the repression of gene transcription [2]. There is much evidence to suggest that lysine acetylation and deacetylation also occur in a large number of non-histone proteins, such as transcription factors and cytoplasmic proteins, and affect not only gene transcription but also other cellular processes [6]. Two types of antagonistic enzymes control the reversibility of lysine acetylation: histone or protein acetylases and histone or protein deacetylases (HDACs) [7]. HDACs are key transcriptional repressors in many diverse physiological and pathological processes. So far, 18 human HDACs have been identified and grouped into four classes. Class I HDACs (HDAC1, 2, 3 and 8) share a high degree of homology with the yeast transcriptional regulator RPD3, class II HDACs are closely related to HDA1 (HDAC4, 5, 6, 7, 9 and 10), class III HDACs, also named sirtuins, are homologous with Sir2 (SIRT1, 2, 3, 4, 5, 6 and 7), and the most recently classified class IV HDAC (HDAC11) is homologous with class I and II enzymes. Class II HDACs are further sub-divided into class IIa forms (HDAC4, 5, 7 and 9) and class IIb forms (HDAC6 and 10) [1,2].
Class IIa HDACs Class IIa HDACs were discovered and cloned by several laboratories in the early 2000s [8–15]. The first surprising feature that justifies their classification within their own sub-family, differentiating them from class I HDACs, is the presence of a long N-terminal domain in addition to their C-terminal catalytic domain (Fig. 1). The N-terminal domain was first
Adaptor and phosphorylation domain
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Fig. 1. Scheme of class IIa HDAC domains.
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most of the studies demonstrating their tissue specificity have employed in vitro experimental approaches, using culture cells. Seminal work from the laboratory of Eric Olson, a pioneer scientist in the field of class IIa HDAC research, has contributed to our understanding of the functions of class IIa HDACs, confirming their role in development and differentiation. Between 2004 and 2006, Olson and his colleagues reported the generation and phenotypic characterization of knockout mice for each class IIa HDAC family member. They reported that mice deficient in HDAC4 display a failure of osteogenesis resulting from premature bone calcification [20]. Mice lacking HDAC5 and/or HDAC9 exhibit exacerbated cardiac hypertrophy in response to stress induced by artificially induced aortic stenosis [21,22]. In addition, mice deficient in HDAC7 show embryonic lethality at day 11, resulting from a failure to form tight junctions in the developing circulatory system [23] (Table 1). Since these initial studies, other researchers in the field have used class IIa HDAC mouse models to investigate further their role as transcriptional repressors in physiology and pathology (Table 1). Their most recent findings are summarized below.
Neuronal physiology and pathology Increasing evidence indicates a crucial role for HDAC4 in physiological and pathological neuronal development and function. In addition to being expressed in muscle and bone, HDAC4 is found at high levels in neurons, where it is mainly located in the cytoplasmic compartment. As mentioned above, mice deficient in HDAC4 show severe skeletal abnormalities and die within 2 weeks of birth. The brains of these mice are 40% smaller than those of their littermate controls. In particular, HDAC4 knockout mice show neuronal developmental defects, such as a smaller cerebellum [24]. Two recent reports have identified an important role for HDAC4 in neuronal synaptic plasticity and memory formation. Kim et al. showed that specific deletion of HDAC4 in the forebrain of mice resulted in the impairment of memory, behavioral learning and long-term synaptic plasticity [25]. Simultaneously, Sando et al. shed light on the mechanisms involved in HDAC4-mediated regulation of synaptic plasticity and memory. They found that, when present in the nucleus, HDAC4 governs the gene transcriptional program characteristic of the central synapsis, affecting information processing in the brain [26]. Interestingly,
Table 1. Phenotypic summary of class IIa HDACs mouse models. Class IIa HDACs mouse model HDAC4 Knockout Conditional knockout in the forebrain Transgenic mice: HDAC4 catalytic mutant in the forebrain HDAC4 knockout in a mouse model of Huntington disease HDAC5 Knockout Knockout Knockout HDAC4 knockout in a mouse model of Alzheimer disease HDAC7 Knockout Conditional knockout in the thymus Transgenic mice: HDAC7 phosphorylation mutant in the thymus HDAC9 Knockout Knockout Knockout HDAC9 knockout in a mouse model of autoimmunity Knockout
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Chondrocyte differentiation defect. Premature bone ossification Small cerebellum, Purkinje cell degeneration Impairment of memory, behavioral learning and long-term synaptic plasticity Defect in spatial learning and memory
20, 24
Delay in the formation of aggregates and rescue of neuronal synaptic function
31
Exacerbated cardiac hypertrophy after stress Decreased axon regeneration after injury Increased sensitivity to cocaine chronic exposure Impairment of memory function
21 33 34 36
Failure to form tight junctions in the developing circulatory system Impairment of positive selection of single-positive (SP) CD4 lymphocytes Block of the negative selection of thymocytes and lethal autoimmune disease
23 41 42
Exacerbated cardiac hypertrophy after stress Increased number of Treg cells Increased resistant to induced colitis Decreased cell proliferation, inflammation, autoantibody production and increased survival of mice Improvement of adipogenic differentiation and systemic metabolic state during an Hight fat diet
22 47 46 48
25 26
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transgenic mice expressing a truncated catalytic domain form of HDAC4 specifically in the forebrain showed a defect in spatial learning and memory [26]. These reports suggest that HDAC4 may be deleted or mutated in human syndromes involving mental retardation. Further reports have described that the HDAC4 locus is in fact deleted or mutated in patients with brachydactyly mental retardation (BDMR) syndrome, which is characterized by intellectual disabilities, developmental delays, behavioral abnormalities and skeletal abnormalities. BDMR syndrome is associated with a deletion in chromosome 2q37 involving the HDAC4 gene [27]. Other clinical cases that do not involve this specific deletion present de novo mutations in HDAC4 [27]. Other reported analyses of cases of familial BDMR syndrome have confirmed the association of HDAC4 mutation or deletion with the pathogenesis of the disease [28]. One of the clinical studies found that HDAC4 was expressed in a mother with mild symptoms of BDMR syndrome, while her son presented a more severe phenotype and lower levels of HDAC4. It is of note that the levels of HDAC4 mRNA were correlated with the severity of the disease, indicating that the phenotype of BDMR syndrome is modulated by HDAC4 in a dose-dependent manner [28]. In a second clinical study, Villavicencio-Lorini et al. investigated a three-generation familial case of BDMR syndrome with microdeletion of chromosome 2q37.3 involving the HDAC4 gene, in which HDAC4 haploinsufficiency was found to be responsible for the patients’ psychomotor and behavioral abnormalities [29]. HDAC4 is also known to be involved in ataxia telangiectasia neurodegenerative disease. It is expressed in the cytoplasm of normal, but is found in the nucleus of Purkinje cells in ataxia telangiectasia patient samples and ataxia-telangiectasia mutated-deficient mice. HDAC4 interacts with the transcription factors MEF2A and cAMP response element binding protein, resulting in an altered gene expression program associated with degeneration [30]. Finally, HDAC4 has also been associated with the pathogenesis of Huntington’s disease. Mielcarek et al. reported that HDAC4 associates with huntingtin and co-localizes with cytoplasmic inclusions [31]. Strikingly, HDAC4 reduction delayed the formation of aggregates in the cytoplasm and rescued neuronal synaptic function in Huntington’s disease mouse models. This correlates with an improvement in motor coordination and increased lifespan [31]. Studies in the laboratory of Valeria Cavalli have indicated the involvement of HDAC5 in axon regeneration, which is essential for rebuilding functional conFEBS Journal 282 (2015) 1736–1744 ª 2014 FEBS
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nections between injured neurons and their targets. Cho and Cavalli showed that axon injury led to tubulin deacetylation, an event that is necessary for axon regeneration and that requires Protein kinase C-mediated activation of HDAC5 [32]. An elegant study performed in the same laboratory subsequently demonstrated that HDAC5 plays a role in axonal regeneration. Axotomy, a type of axon injury, in cultured dorsal root ganglion neurons induces the nuclear export of HDAC5 in a calcium- and Protein kinase C mu-dependent manner, leading to increased histone acetylation and activation of a pro-regenerative gene transcription program [33]. The cytoplasmic accumulation of HDAC5 is necessary for axon regeneration as expression of an HDAC5 phosphorylation mutant that is always located in the nuclear compartment interferes with axon regeneration [33]. HDAC5 has also been linked to the behavioral response to cocaine. Histone acetylation is altered in animal models of drug addiction. After chronic exposure to cocaine in mice, HDAC5 becomes phosphorylated and shows decreased activity in the nucleus accumbens, a major brain reward region. Strikingly, HDAC5-deficient mice are more sensitive than wild-type controls to the chronic effects of cocaine [34]. More recently, Taniguchi et al. shed light on the molecular mechanisms by which cocaine modulates HDAC5 function. They found that cAMP signaling leads to dephosphorylation and transient nuclear accumulation of HDAC5 in the nucleus accumbens, suppressing the development of cocaine reward behavior in vivo [35]. HDAC5 has also been reported to play a role in Alzheimer’s disease: HDAC5 deficiency in a mouse model for Alzheimer’s disease impairs memory function [36]. Recently, HDAC9 has also been linked to neuronal physiology and pathology. Sugo et al. reported that HDAC9 is expressed in the mouse cerebellar cortex during postnatal cortical development [37]. After spontaneous neuronal activity, HDAC9 is exported to the cytoplasm in postnatal cortical neurons, leading to expression of the gene c-Fos and promoting dendritic growth [37]. Whether neuronal development is compromised in HDAC9-deficient mice remains to be established. In the context of neuronal pathology, HDAC9 has been associated with schizophrenia. Lang et al. recently reported that HDAC9 is hemizygously deleted in patients with schizophrenia [38]. Strikingly, the authors observed that HDAC9 is widely expressed in areas of the mouse brain associated with the neuropathology of schizophrenia, and the expression is exclusively detected in post-mitotic neurons, indicating that HDAC9 may be crucial to the correct function of mature neurons [38].
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Taken together, these studies indicate that HDAC4, HDAC5 and HDAC9 may be promising therapeutic targets in diverse human neurological disorders and diseases.
The immune system Studies from the laboratory of Eric Verdin indicated that, among the various class IIa HDACs, HDAC7 was highly expressed in developing thymocytes at the CD4+ CD8+ double-positive stage [12]. Under basal conditions, HDAC7 localizes to the nucleus of thymocytes, where it exerts transcriptional repressive functions [12,39]. In this context, HDAC7 was found to repress the transcription of the orphan nuclear receptor Nur77, leading to the inhibition of apoptosis or negative selection of T cells [12]. After T-cell receptor activation, HDAC7 becomes phosphorylated at conserved serine residues located in its N-terminal region and is exported to the cytoplasm, resulting in derepression of Nur77 and induction of apoptosis [40]. HDAC7 was subsequently reported to be involved not only in repression of Nur77, but also in the transcriptional regulation of a large number of genes involved in both positive and negative selection of thymocytes [39]. More recently, Kasler et al. presented definitive evidence for the role of HDAC7 in T-cell development. First, using a conditional knockout mouse model, they demonstrated that specific deletion of HDAC7 in double-positive thymocytes results in a significant reduction in survival or positive selection of single-positive CD4+ lymphocytes [41]. Microarray analysis showed that HDAC7 deficiency in thymocytes leads to the de-regulation of the genetic program characteristic of CD4+ single-positive T cells. Second, a transgenic mouse model expressing an HDAC7 phosphorylation mutation that cannot be exported to the cytoplasm in thymocytes revealed the relevance of the signal-dependent repressive function of HDAC7. These mice showed a profound block of the negative selection of thymocytes, leading to escape of autoreactive T cells to the periphery, and a lethal autoimmune disease in the exocrine pancreas and other organs [42]. Gene expression profiling showed that the HDAC7 phosphorylation mutation suppressed the gene expression program characteristic of negative selection of thymocytes. In a recent paper, Liu et al. established a link between HDAC7 and autoimmune disease in humans. The authors identified novel risk and susceptibility loci for primary sclerosing cholangitis, a severe autoimmune disease of the liver. Interestingly, one of the risk loci associated with the disease comprised the HDAC7 gene, indicating its role in primary sclerosing cholangitis etiology [43]. Whether 1740
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HDAC7 is involved in other human autoimmune diseases remains to be established. The relevance of HDAC7 in T-cell biology has recently been confirmed. Using a quantitative proteomic approach to identify the phosphoproteome of cytotoxic T cells, Navarro et al. showed that HDAC7 is constitutively phosphorylated and localized in the cytoplasm of this type of lymphocyte [44]. This is crucial for the proper function of cytotoxic T cells, as expression of a phosphorylation-deficient mutant of HDAC7 that is always localized in the nucleus interfered with the proliferation capacity of cytotoxic T cells [44]. It has recently been reported that, in addition to its expression in thymocytes, HDAC7 is found at high levels in B lymphocytes but is not present in myeloid cells such as macrophages [45]. Using an immune cellular reprogramming system, we found that HDAC7 is down-regulated during the conversion of pre-B cells into macrophages [45]. Exogenous expression of HDAC7 in this system interfered with the acquisition of essential macrophage-specific cell functions. Moreover, gene expression analysis demonstrates that reexpression of HDAC7 interferes with the establishment of the myeloid gene transcriptional program [45]. From a mechanistic point of view, we reported that HDAC7 interacts with the transcription factor MEF2C and is recruited to the promoter of macrophage genes in Bcell precursors. siRNA-mediated knockdown of HDAC7 leads to the de-repression of myeloid genes in B lymphocytes, indicating that HDAC7 may be an essential transcriptional repressor of lineage-inappropriate genes in B cells. A role for HDAC7 in B-cell development in in vivo mouse models remains to be established. Together, the recent reports suggest that HDAC7 is a lymphoid-specific transcriptional repressor that is involved in regulating several crucial aspects of B- and T-cell biology and development. Over the last few years, HDAC9 has also emerged as a crucial transcriptional repressor in the immune system. It is highly expressed in regulatory T cells (Treg cells), which are an important subset of T lymphocytes that limit immune responses and are critical for maintaining immune self-tolerance. Treg lymphocytes are characterized by expression of the transcription factor FOXP3 that mediates gene activation and repression. HDAC9 is highly expressed in human Treg cells and interacts with FOXP3 [46]. In the mouse, HDAC9 was also found to be specifically expressed in Treg cells and localized in the nucleus of resting cells, but was exported to the cytoplasm after T-cell receptor activation. Definitive proof that HDAC9 controls Treg function was obtained from a knockout mouse model. HDAC9-deficient mice had 50% more FOXP3-positive FEBS Journal 282 (2015) 1736–1744 ª 2014 FEBS
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cells than wild-type mice, and Treg cells lacking HDAC9 were found to be more suppressive than the control cells [47]. The authors also reported a function of HDAC9 in inflammatory bowel diseases such as colitis, in which Treg cells are known to play a crucial role. HDAC9-deficient mice were resistant to colitis induced by dextran sulfate sodium [47]. More recently, using colitis mouse models, de Zoeten et al. reported that Treg cells deficient in HDAC9 exhibit stronger repressive functions due to their greater ability to survive and proliferate [46]. HDAC9 functions have also been found to be associated with systemic autoimmunity. Yan et al. recently discovered that HDAC9 is highly expressed in various subsets of CD4+ T cells in autoimmune Murphy-Roths Lymphoma/Lymphoproliferative (MRL/lpr) mice as well as in CD4+ T cells of lupus patients [48]. Interestingly, HDAC9 deficiency in MRL/lpr mice gave rise to decreased cell proliferation, inflammation, auto-antibody production and increased survival of mice [48].
Energy metabolism and obesity Recently, two elegant studies have established a link between class IIa HDACs and energy/glucose metabolism. Mihaylova et al. reported that HDAC4, 5 and 7 are expressed in the liver, where they are phosphorylated by activated protein kinase family kinases and located in the cytoplasm [49]. However, in response to glucagon, a fasting hormone, they become dephosphorylated and translocate into the nucleus, where they are recruited to the promoters of gluconeogenic enzymes such as glucose-6-phosphatase-a. From a mechanistic point of view, HDAC4 and HDAC5 interact with the class I HDAC HDAC3, leading to the deacetylation and activation of Forkhead box class O (FOXO) family transcription factors and expression of their target genes. Knockdown of class IIa HDACs in murine liver cells results in inhibition of FOXO target genes, lowers blood glucose levels, and increases glycogen storage. Finally, class IIa HDAC knockdown in mouse models of type 2 diabetes ameliorates hyperglycemia, suggesting that inhibitors of class I/II HDACs may be potential therapeutic agents for treating metabolic syndrome [49]. In a parallel study using Drosophila as a model system, Wang et al. found that, under feeding conditions, HDAC4 is phosphorylated by salt-inducible kinase 3 (SIK3) and located in the cytoplasm [50]. However, during fasting, SIK3 becomes inactivated, resulting in the dephosphorylation and nuclear translocation of HDAC4, and FOXO deacetylation. SIK3 mutant flies are starvation-sensitive, reflecting FOXO-dependent increases in lipolysis that deplete triglyceride stores. FEBS Journal 282 (2015) 1736–1744 ª 2014 FEBS
Reducing HDAC4 levels restores lipid accumulation [50]. Studies in class IIa HDAC-deficient mice are required to further elucidate their role in metabolic processes. Recent reports have linked HDAC9 function to adipogenesis. Differentiation of pre-adipocytes into mature and functional adipocytes is a fundamental mechanism in obesity. HDAC9 was reported to be down-regulated before adipogenic differentiation. HDAC9-deficient pre-adipocytes show accelerated adipogenic differentiation, indicating that HDAC9 may act as a negative regulator of adipogenesis [51]. Very recently, the same laboratory demonstrated a role for HDAC9 in obesity [52]. In response to chronic caloric excess, the differentiation of pre-adipocytes into functional adipocytes is compromised. After administration of a chronic high-fat diet in mice, HDAC9 deficiency was found to result in improvement of adipogenic differentiation and establishment of a systemic metabolic state [52]. In the absence of HDAC9, mice on a high-fat diet experience diminished weight gain, and have improved glucose tolerance and insulin sensitivity and reduced hepatosteatosis [52]. Taken together, these findings indicate that HDAC9 may be a promising therapeutic target for combating obesity-related metabolic diseases.
Concluding remarks The existence of 18 mammalian HDACs indicates that they may play highly specific roles in an organism under normal and pathological circumstances. Indeed, gene deletion for individual HDACs in mice has confirmed their highly specific biological functions. This is particularly evident for class IIa HDACs. Since their discovery 14 years ago, we have learnt that they are enzymes of considerable importance in development and differentiation. More recent studies indicate that they may be involved in human diseases or disorders that affect the tissues and organs in which they are expressed. Therefore, class IIa HDACs appear to be promising therapeutic targets. Human genetics approaches, including next-generation ultra-sequencing techniques, will enable us to measure class IIa HDAC expression levels as well as understand their patterns of mutation and deletion in human disease. Finally, given the specificity of each of these enzymes, the development of isoform-specific HDAC inhibitors or modulators is of central importance to discriminate between the types of HDACs and to target only the enzymes involved in a particular pathological situation. Responding to this challenge will shape future therapeutic approaches to patients with specific diseases.
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Acknowledgements This work was supported by grant SAF2011-28290 from the Spanish Ministry of Economy and Competitiveness (MINECO).
Author contribution
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Maribel Parra wrote the review.
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