SURVIVIN IN SYNERGY WITH BAF/SWI COMPLEX BINDS BIVALENT CHROMATIN REGIONS AND ACTIVATES DNA DAMAGE RESPONSE IN CD4+ T CELLS

Abstract

AbstractThis study explores a regulatory role of oncoprotein survivin on the bivalent regions of chromatin (BvCR) characterized by concomitant deposition of trimethylated lysine of histone H3 at position 4 (H3K4me3) and 27 (H3K27me3).Intersect between BvCR and chromatin sequences bound to survivin demonstrated their co-localization oncis-regulatory elements of genes which execute DNA damage control in primary human CD4+cells. Survivin anchored BRG1-complex to BvCR to repress DNA damage repair genes in IFNγ-stimulated CD4+cells. In contrast, survivin inhibition shifted the functional balance of BvCR in favor of H3K4me3, which activated DNA damage recognition and repair. Co-expression of BRG1, survivin and IFNγ in CD4+cells of patients with rheumatoid arthritis identified arthritogenic BRG1hicells abundant in autoimmune synovia. Immunomodulating drugs inhibited the subunits anchoring BRG1-complex to BvCR, which changed the arthritogenic profile.Together, this study demonstrates the function of BvCR in DNA damage control of CD4+cells offering an epigenetic platform for survivin and BRG1-complex targeting interventions to combat autoimmunity.SummaryThis study shows that bivalent chromatin regions accommodate survivin which represses DNA repair enzymes in IFNγ-stimulated CD4+T cells. Survivin anchors BAF/SWI complex to these regions and supports autoimmune profile of T cells, providing novel targets for therapeutic intervention.