Chromatin regulation by Brg1 underlies heart muscle development and disease

Abstract

SUMMARYCardiac hypertrophy and failure are characterized by transcriptional reprogramming of gene expression. Adult cardiomyocytes in mice express primarily α-myosin heavy chain (α-MHC), whereas embryonic cardiomyocytes express β-MHC. Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from α-MHC to fetal β-MHC expression. Here we show that Brg1, a chromatin-remodeling protein, plays critical roles in regulating cardiac growth, differentiation and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining BMP10 and suppressing p57kip2 expression. It preserves fetal cardiac differentiation by interacting with HDAC and PARP to repress α-MHC and activate β-MHC. In adults, Brg1 is turned off in cardiomyocytes. It is reactivated by cardiac stresses and complexes with its embryonic partners, HDAC and PARP, to induce a pathological α- to β-MHC shift. Preventing Brg1 re-expression decreases hypertrophy and reverses such MHC switch. Brg1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Our studies show that Brg1 maintains cardiomyocytes in an embryonic state, and demonstrate an epigenetic mechanism by which three classes of chromatin-modifying factors, Brg1, HDAC and PARP, cooperate to control developmental and pathological gene expression.

Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development

“…BAF complexes have been shown to interact with HDACs and function as corepressors in various contexts (21,36). We found that endogenous HDAC1 and HDAC2 coprecipitated with BAF complexes in MEFs when antibodies against Brg or BAF57 were used for IP (Fig.…”

“…In addition, their 10-12 subunits provide surfaces to interact with various transcription factors and cofactors (21,22), which may introduce additional ATPase-independent functions to BAF complexes as activators or repressors.…”

Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

“…Measuring the luciferase activity driven by PlexinA2 reporter revealed that Brg1 activated the PlexinA2 fulllength promoter activity by 3.24-fold. Deletional analysis (35) of PlexinA2 promoter showed a length-dependent induction of promoter activities by Brg1, with 4.01-fold for the (−5754, +463) promoter, 2.70-fold for the (−2103, +463) promoter, and 1.55-fold for the (−193, +463) promoter (Fig. 4N), suggesting Brg1 activity on multiple binding sites (p1-p9).…”

“…4H). ChIP-qPCR analyses of cardiac neural crest tissues (∼25-30 embryos per ChIP reation) using anti-Brg1 antibody (35,36) showed that Brg1 was highly enriched within the conserved p1-p9 regions, but not in the nonconserved region of PlexinA2 (Fig. 4 I and J).…”

“…The pREP4 plasmid is an Epstein-Barr virus-based episomal vector that undergoes chromatinization after transfection into mammalian cells (37) and thus is suitable for studying the chromatin and transcription activity of Brg1 on gene promoters (35)(36)(37). Given the resistance of Joma1.3 NCCs to transfection, the PlexinA2 reporter plasmids and Brg1-expressing plasmids (35) were cotransfected into 293T cells as a surrogate for reporter assays. Measuring the luciferase activity driven by PlexinA2 reporter revealed that Brg1 activated the PlexinA2 fulllength promoter activity by 3.24-fold.…”