REVIEWS in-containing p ein 3(MID also know The gene encoding as KDM6B) been implicated in the reo 0 nt of t ha ms in A2 that are angiogenesi ummar there is a growing body of mole ula m in sclinical evidenceto suggest that these mechanismsn targe The ad exhibit Metabolic disarders The sirtuins which deacetvlate both substrates are majo which then been associated with a lower body mass index in tw nato ctivity of SIRTI has been as "and in diabetes in huma dies have revealed that several specific HDACs are have favourable phv une respons heindirectactne IRT HDAC6 and HDAC9 enhan f the tran rate studyon-em erebro entriculr infusion o box P3 to promo the activit diet-i obe betic mice norm antigen-pres RNA the immun D01 e by SIRT stoe methylatio coatributestomypergyCaerm -tra slational modificati of the e NF-xBp65 sub (SETD7) variegation and by and suppr 63 f th oth through acetylation of h s and th ugh tran the ation of the i mune r ponse Regenerative medicine:role in er nic stem cell differ alyt al in th lysine temic global iclhrynthedirecteddfie iation ofembryonic histone lysine methylation in the ofimmun of induced pluripotent stem cells by rep ammin ch the the protein methyltransteras mportant ted wit silen ment of diabetes and neu as P ns d ted w ith pu NATURE REVIEWSIDRUG DISCOVERY VOLUME 11 MAY 2012 389Jumonji domain A conserved domain originally identified in the Jumonji family of transcription factors, now known to be histone demethylases. The Jumonji C domain comprises the catalytic domain of the 2-oxoglutarate-dependent lysine demethylases. Hyperglycaemic memory A phenomenon in which the deleterious end-organ effects resulting from exposure to high glucose levels persist for several years after usual glycaemic control is restored. Merck)64 and MS-275 (REF. 65) are revealing great insights into the role of these HDACs in central nervous system pathologies. Schizophrenia is another disorder in which there are altered levels of epigenetic proteins. The gene encoding SMARCA2 (SWI/SNF-related matrix-associated actin￾dependent regulator of chromatin subfamily A member 2) expresses BRM, which is a protein component of the SWI/ SNF chromatin-remodelling complex; this complex has been associated with schizophrenia in genome-wide asso￾ciation studies. Polymorphisms in SMARCA2 that are linked to the disease produce changes in the expression of the gene and/or in the encoded amino acid sequence66. In addition, a polymorphism in BRD1 has been shown to be associated with schizophrenia and bipolar affective disorder67. Inflammation. The adaptive immune response exhibits hallmarks of a system that is subject to epigenetic regu￾lation. The adaptive immune system is composed of multipotent precursor cells that undergo differentiation and clonal expansion upon exposure to an appropriate stimulus (for example, an antigen) to become activated lymphocytes, which then retain a memory against future exposure. It is therefore unsurprising that non-selective HDAC inhibitors have demonstrated preclinical efficacy in several rodent models of inflammatory conditions, both in rodent disease models68 and in clinical samples taken from patients with autoimmune disease69. These studies have revealed that several specific HDACs are implicated in various aspects of the immune response, including the innate and adaptive system70. For example, HDAC6 and HDAC9 enhance the activity of the tran￾scription factor forkhead box P3 to promote the activity of anti-inflammatory regulatory T lymphocytes71, whereas HDAC6 has recently been implicated in the differentiation and maturation of antigen-presenting dendritic cells72. In addition, several sirtuins have been shown to regu￾late the immune response by modulating the activity of key transcription factors. For example, SIRT1 and SIRT6 modulate nuclear factor-κB (NF-κB) activity via post-translational modification of the NF-κB p65 sub￾unit and by altering the accessibility of the promoters to p65, respectively73. Accordingly, SIRT1 activators have anti-inflammatory effects in in vitro and in vivo models of inflammation74. Several HATs also regulate the inflammatory response, both through acetylation of histones and through tran￾scription factors such as NF-κB75. These findings clearly indicate an important role for acetylation in the regu￾lation of the immune response; this is further supported by recent findings indicating that the BET family of bromodomain-containing proteins is pivotal in the systemic global inflammatory response to endotoxin76. In addition, there is growing evidence of a role for histone lysine methylation in the regulation of immune processes. In particular, the protein methyltransferase G9A (also known as EHMT2) is important in mediating the silencing of specific genes during endotoxin shock via H3K9 dimethylation77. The flavin-dependent amine oxidase LSD2 mediates NF-κB demethylation and, in doing so, it has been implicated in a regulatory circuit that controls the expression of pro-inflammatory genes in dendritic cells78. Moreover, the histone demethylase Jumonji domain-containing protein 3 (JMJD3; also known as KDM6B) has been implicated in the response of macrophages to lipopolysaccharides and in the activa￾tion and maintenance of so-called ‘alternatively acti￾vated’ macrophages, which are thought to be involved in the host response to parasites, tissue remodelling and angiogenesis79,80. In summary, there is a growing body of molecular and pharmacological evidence that epigenetic machinery is involved in the regulation of the immune system via mechanisms that involve modulation of transcription factors and modification of histones. In addition, there is clinical evidence to suggest that these mechanisms may be deregulated in autoimmune diseases81,82; targeting epigenetic regulators may therefore represent powerful new approaches for the amelioration of these conditions. Metabolic disorders. The sirtuins, which deacetylate both histone and non-histone substrates, are major regulators of metabolism83. Two common variants in SIRT1 have been associated with a lower body mass index in two independent Dutch populations. Carriers of these vari￾ants have a reported 13–18% decreased risk of obesity84. Reduced levels or reduced activity of SIRT1 has been asso￾ciated with complications of type 2 diabetes in humans85 and mice86. Thus, activation of one or more sirtuins can have favourable physiological effects. Resveratrol, through the indirect activation of SIRT1, stimulates insulin release in insulinoma INS-1E cells and human islets87. In a sepa￾rate study, long-term intracerebroventricular infusion of resveratrol to diet-induced obese diabetic mice normal￾ized hyperglycaemia and improved hyperinsulinaemia88. These effects were also reported to be mediated via SIRT1, as demonstrated by knockdown of the protein using short hairpin RNA89. Histone methylation contributes to hyperglycaemic memory in models of transient hyperglycaemia90. The methyltransferases SET domain-containing protein 7 (SETD7) and suppressor of variegation 3–9 homolog 1 (SUV39H1), as well as the demethylase LSD1, contribute to sustained upregulation of the gene encoding the p65 subunit of NF-κB in response to glucose. Knockdown of SETD7 reverses effects that are associated with diabetic vascular injury, suggesting that this protein lysine methyl￾transferase (PKMT) is a potential target for the treatment of diabetes91. Regenerative medicine: role in embryonic stem cell differ￾entiation and reprogramming. Modulation of epigenetic proteins has shown utility in regenerative medicine, par￾ticularly in the directed differentiation of embryonic stem cells towards a committed lineage, and in the formation of induced pluripotent stem cells by reprogramming somatic cells92. Important opportunities associated with HDAC proteins in regenerative medicine are in the treat￾ment of diabetes and neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Stem cells treated with putative HDAC inhibitors demonstrated REVIEWS NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | MAY 2012 | 389 © 2012 Macmillan Publishers Limited. All rights reserved