Epigenetic Mechanism Of Type II Transactivator (CIITA) Regulating Cellular Gene Expression

Metabolic homeostasis is achieved through balanced energ? storage and output.Impairment of energ? expenditure is a hallmark event in patients with obesit? and t?pe 2 diabetes.The NAD+-dependent histone deacet?lase SIRT1,b? regulating the acet?lation of nuclear transcription factors involved in energ? metabolism,has been implicated as an important modulator in the pathogenesis of t?pe 2 diabetes.Previousl? we have shown that the pro-inflammator? c?tokine interferon gamma(IFN-?)disrupts energ? expenditure in skeletal muscle cells via h?permeth?lated in cancer 1(HIC1)-class ? transactivator(C?T A)dependent repression of SIRT1 transcription.Here we report that repression of SIRT1 transcription b? IFN-? paralleled loss of histone acet?lation on the SIRT1 promoter region with simultaneous recruitment of histone deacet?lase 4(HDAC4).IFN-?activated HDAC4 in vitro and in vivo b? up-regulating its expression and stimulating its nuclear accumulation.HIC1 and C?TA recruited HDAC4 to the SIRT1 promoter and cooperated with HDAC4 to repress SIRT1 transcription.HDAC4 depletion b? small interfering RNA or pharmaceutical inhibition normalized histone acet?lation on the SIRT1 promoter and restored SIRT1 expression in the presence of IFN-?.Over-expression of HDAC4 suppressed the transcription of genes involved in energ? expenditure in a SIRT1-dependent manner.In contrast,HDAC4 knockdown/inhibition neutralized the effect of IFN-? on cellular metabolism b? normalizing SIRT1 expression.Therefore,our data reveal a role for HDAC4 in regulating cellular energ? output and as such provide insights into rationalized design of novel anti-diabetic therapeutics.Class ? major histocompatibilit? complex(MHC ?)dependent antigen presentation serves as a ke? step in mam-malian adaptive immunit? and host defense.In antigen presenting cells(e.g.,macrophages),MHC ? transcription can be activated b? interferon gamma(IFN-?)and mediated b? class ? transactivator(CUTA).The underl?ing epi-genetic mechanism,however,is not completel? understood.Here we report that following IFN-? stimulation,s?mmetricall? dimeth?lated histone H3 arginine 2(H3R2Me2s)accumulated on the MHC ? promoter along with CUTA.IFN-? augmented expression,nuclear translocation,and promoter binding of the protein arginine meth?ltransferase PRMT5 in macrophages.Over-expression of PRMT5 potentiated IFN-? induced activation of MHC ? transcription in an enz?me activit?-dependent maimer.In contrast,PRMT5 silencing or inhibition of PRMT5 activit? b? meth?lthioadenosine(MTA)suppressed MHC ? transactivation b? IFN-?,C?TA interacted with and recruited PRMT5 to the MHC ? promoter and mediated the s?nerg? between PRMT5 and ASH2/ WDR5 to activate MHC ? transcription.PRMT5 expression was down-regulated in senescent and H202-treated macrophages rendering ineffectual induction of MHC ? transcription b? IFN-?.Taken together,our data reveal a pathoph?siologicall? relevant role for PRMT5 in MHC ? transactivation in macrophages.