Epigenetic Regulatory Mechanisms Of Gene Activation During Cellular Stress

ATP-dependent SWI/SNF chromatin remodeling complexes can play either an active or a repressive role in the expression of mammalian genes. The ATPase subunits, hBrm and Brgl, of SWI/SNF complexes are exclusive; only one of the two is found in a remodeling complex. Despite the fact that their functions in cell growth, apoptosis and development can be redundant, distinct or even opposing, their roles during environmental and physiological stresses remain unclear. Here we studied the regulatory role of the hBrm and Brgl subunits of SWI/SNF complexes on human genes via a specific IFNy-activated sequence, GAS, in the gene promoters. We showed that an hBrm-to-Brgl switch at GAS mediates an activation of the gene upon heat shock or under IFN-y treatment. The switch is initiated by the acetylation of hBrm that dissociates from the mSin3a-HDAC co-repression complex and then releases from the GAS. This is followed by the recruiting of Brgl by phosphorylated Statl that directs an open chromatin conformation at the promoter and elicits an efficient expression of the gene. Our findings provide an example of how hBrm first preferentially interact with repression complex followed by the Brgl recruiting and an activation of human genes in response to heat shock and IFNy and sheds lights on the reconstitution of immune function via thermal therapy in vivo.The heat shock element in the first intron of human hsp90βgene (iHSE) acts as an intronic enhancer to bind the heat shock factor (HSF1) and activates hsp90βgene under heat shock. Here, we show that, in addition to the HSF1, Stat1 phosphorylation is indispensable in the event. We show that Jak2, a Janus kinase specifically associated with the (3 subunit of IFN-y receptor, and PKCs, an isoform of the atypical PKC family, are the two dominant kinases responsible for the heat shock induced phosphorylation on Y701 and S727 of Statl. However, the activation of these kinases under heat shock requires the association of chaperone proteins of the Hsp90 family, in particular, the Hsp90βunder heat shock. Furthermore, Brgl, an ATPase subunit of the SWI/SNF chromatin remodeling complex is recruited by Statl and HSF1 at the iHSE under heat shock. Brgl further confers an open chromatin conformation at the promoter region, which is pivotal to the heat shock induced fully activation of the hsp90βgene in Jurkat cells. This is a novel example of how multiple activation steps occur under heat shock, first on the kinases and then the Statl and the SWI/SNF chromatin remodeling complex that follows to conduct an auto-regulation based fully activation of the gene.