Chromatin regulation by Brg1 underlies heart muscle development and disease.
Chromatin regulation by Brg1 underlies heart muscle development and disease.
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作者：
心脏肥大和衰竭的特征是基因表达的转录重编程。小鼠成年心肌细胞主要表达 α-肌球蛋白重链 (α-MHC)，而胚胎心肌细胞则表达 β-MHC。心脏应激会引发成人心脏肥大，并从 α-MHC 表达转变为胎儿 β-MHC 表达。在这里，我们证明了 Brg1，一种染色质重塑蛋白，在调节心脏生长、分化和基因表达中发挥着关键作用。在胚胎中，Brg1 通过维持 BMP10 和抑制 p57kip2 表达来促进心肌细胞增殖。它通过与 HDAC 和 PARP 相互作用来抑制 α-MHC 并激活 β-MHC，从而保留胎儿心脏分化。在成人中，心肌细胞中的 Brg1 被关闭。它通过心脏应激和与其胚胎伙伴 HDAC 和 PARP 的复合物重新激活，从而诱导病理性 α-MHC 向 β-MHC 转变。阻止 Brg1 重新表达可减少肥大并逆转此类 MHC 开关。 Brg1 在某些肥厚型心肌病患者中被激活，其水平与疾病严重程度和 MHC 变化相关。我们的研究表明，Brg1 将心肌细胞维持在胚胎状态，并证明了三类染色质修饰因子 Brg1、HDAC 和 PARP 合作控制发育和病理基因表达的表观遗传机制。
Cardiac 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.
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DOI：
10.1152/ajpheart.01124.2005
发表时间：
2006-10-01
影响因子：
4.8
作者：
Pillai, Jyothish B.;Gupta, Madhu;Gupta, Mahesh P.
通讯作者：
Gupta, Mahesh P.
影响因子：
5.7
作者：
Abraham, WT;Gilbert, EM;Bristow, MR
通讯作者：
Bristow, MR
影响因子：
9
作者：
MORROW, AG;BROCKENBROUGH, EC
通讯作者：
BROCKENBROUGH, EC
影响因子：
20.1
作者：
Kinugawa, K;Yonekura, K;Simpson, PC
通讯作者：
Simpson, PC
影响因子：
64.5
作者：
Liu, R;Liu, H;Zhao, KJ
通讯作者：
Zhao, KJ