BRG1-mediated immune tolerance: facilitation of Treg activation and partial independence of chromatin remodelling

Abstract

Treg activation in response to environmental cues is necessary for regulatory T cells (Tregs) to suppress inflammation, but little is known about the transcription mechanisms controlling Treg activation. We report that despite the known proinflammatory role of the chromatin-remodelling factor BRG1 in CD4 cells, deleting Brg1 in all ab T cell lineages led to fatal inflammation, which reflected essential roles of BRG1 in Tregs. Brg1 deletion impaired Treg activation, concomitant with the onset of the inflammation. Remarkably, as the inflammation progressed, Tregs became increasingly activated, but the activation levels could not catch up with the severity of inflammation. In vitro assays indicate that BRG1 regulates a subset of TCR target genes including multiple chemokine receptor genes. Finally, using a method that can create littermates bearing either a tissue-specific point mutation or deletion, we found the BRG1 ATPase activity partially dispensable for BRG1 function. Collectively, these data suggest that BRG1 acts in part via remodelling-independent functions to sensitize Tregs to inflammatory cues, thus allowing Tregs to promptly and effectively suppress autoimmunity.

Polycomb Repressive Complex 2 Confers BRG1 Dependency on the CIITA Locus

“…CBP and p300 are recruited to CIITA (11), but the identity of the H3 methyl transferase is unknown, and the mechanism by which BRG1 and PRC2 influence recruitment of these enzymes also requires additional analysis. BRG1 can have ATPase-independent effects (35,36), but CIITA induction requires enzyme activity (7), suggesting that nucleosome movement is required for transferase recruitment.…”

BPTF Is Essential for T Cell Homeostasis and Function

“…Yet, over-exuberant T cell function contributes to autoimmune and inflammatory disease. Chromatin remodeling complexes are required for thymic T cell development (19) by integrating signaling from TCR and co-stimulatory molecules (20, 21). In particular, Brg, the ATPase subunit of BAF complex, is critical for the development of double negative thymic T cells and Th1/Th2 cell differentiation (22–24).…”

“…In particular, Brg, the ATPase subunit of BAF complex, is critical for the development of double negative thymic T cells and Th1/Th2 cell differentiation (22–24). Nonetheless, Brg is largely dispensable for the homeostasis of mature T cell (19). These findings suggest that chromatin-remodeling complexes, such as Brg containing BAF complex, control T cell function in a cell-type specific manner.…”

ATP-dependent chromatin remodeling during mammalian development

“…CD4 repression depends on a 434 bp transcriptional silencer region, and both BRG1 and BAF57 increase chromatin accessibility by reducing H1 linker histone content and facilitating the binding of RUNX1, a transcriptional repressor, to this silencer region (Wan et al, 2009). BRG1 is also involved in CD4 activation and regulatory T-cell activation, which partially require its chromatin-remodeling ability and physical interactions between BRG1 and the Cd4 locus (Chaiyachati et al, 2013;Jani et al, 2008).…”

“…Differentiation to neurons , lymphocytes (Chi et al, 2003), adipose tissue (Pedersen et al, 2001), heart tissue (Hang et al, 2010;Stankunas et al, 2008;Takeuchi et al, 2011). Differentiation of hair follicles , Schwann cells (Weider et al, 2012), thymocytes (Chaiyachati et al, 2013;Jani et al, 2008), melanocytes and blood cells (Wiley et al, 2015;Willis et al, 2012) BRM (Smarca2) Embryogenesis (Smith-Roe and Bultman, 2013), smooth muscle tissue development (Zhang et al, 2011), differentiation and development of vasculature and vascular integrity (Wiley et al, 2015;Xu and Fang, 2012), skeletal muscle development (Albini et al, 2015), metabolic homeostasis in cardiomyocytes (Banerjee et al, 2015) ARID1 members BAF250A (Arid1a) Regulates nucleosome occupancy during ESC differentiation , controls hematopoietic progenitor pool (Krosl et al, 2010) and cardiac precursor differentiation from second heart field cells (Lei et al, 2012) BAF250B (Arid1b) Maintenance of ESC pluripotency (Yan et al, 2008) PBAF complex BAF200 (Arid2) Heart morphogenesis and coronary artery development (He et al, 2014), osteoblast differentiation …”