HDAC9

Abstract: Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (Treg cells). Although Treg cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal Treg function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced Treg-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through Treg-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, Treg-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3 + Treg cells. Eukaryotic DNA wound around histone octamers forms nucleosomes that are themselves folded into higher-ordered chromatin structures 1 . Core histones have N-terminal tails extending from compact nucleosomal cores that affect histone interaction and gene regulation. Histone acetyltransferases (HAT) acetylate, and histone/protein deacetylases (HDAC) deacetylate, e-acetyllysine residues of these histone tails. HATs generally increase accessibility and promote gene transcription, whereas HDACs typically dampen histone-DNA and histone– nonhistone protein interactions 2,3 , though exceptions occur 4–6 .H ATs and HDACs also regulate the functions of nonhistone proteins 7 ,a s first described for p53 (ref. 8). An HDACi occupies HDAC catalytic sites, blocking substrate access and causing increased histone acetylation and gene transcription. Although HDACis are under intensive study as anticancer therapies 2 , they also have antiinflammatory effects 9 .H ere we show that HDACi administration increases Foxp3 expression as well as the numbers and function of Foxp3-dependent Treg cells, providing a means to pharmacologically enhance the suppressive properties of Treg cells in vitro and in vivo. RESULTS HDACi use boosts thymic production of natural Foxp3 + Treg cells Treatment of mice with an HDACi, trichostatin-A (TSA) 10 ,i ncreased the proportions and absolute numbers of Foxp3 + CD4 + T cells in

Abstract: The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic β-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development.