From the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, China (Y.L., S.A., C.L., X.L., Y.Y., C.-Y.L., A.H.).
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China (X.Y., A.H.).
Circ Res. 2019 Jul 5;125(2):198-208. doi: 10.1161/CIRCRESAHA.118.314366. Epub 2019 May 20.
Replication-independent histone turnover has been linked to cis-regulatory chromatin domains in cultured cell lines, but its molecular underpinnings and functional relevance in adult mammalian tissues remain yet to be defined.
We investigated regulatory functions of replication-independent histone turnover in chromatin states of postmitotic cardiomyocytes from adult mouse heart.
We used H2B-GFP (histone 2B-green fluorescent protein) fusion protein pulse-and-chase approaches to measure histone turnover rate in mouse cardiomyocytes. Surprisingly, we found that the short histone half-life (≈2 weeks) contrasted dramatically with the long lifetime of cardiomyocytes, and rapid histone turnover regions corresponded to cis-regulatory domains of heart genes. Interestingly, recruitment of chromatin modifiers, including Polycomb EED (embryonic ectoderm development), was positively correlated with histone turnover rate at enhancers. Mechanistically, through directly interacting with and engaging the BAF (BRG1 [Brahma-related gene-1]-associated factor) complex for nucleosome exchange for stereotyped histone modifications from the free histone pool, EED augmented histone turnover to restrain enhancer overactivation.
We propose a model in which replication-independent histone turnover reinforces robustness of local chromatin states for adult tissue homeostasis.
在培养的细胞系中，与顺式调控染色质域相关的复制独立的组蛋白周转已经被证实，但在成年哺乳动物组织中，其分子基础和功能相关性仍有待确定。
我们研究了复制独立的组蛋白周转在成年小鼠心脏的有丝分裂后心肌细胞的染色质状态中的调控功能。
我们使用 H2B-GFP（组蛋白 2B-绿色荧光蛋白）融合蛋白脉冲追踪方法来测量小鼠心肌细胞中的组蛋白周转率。令人惊讶的是，我们发现短的组蛋白半衰期（≈2 周）与心肌细胞的长寿命形成鲜明对比，快速的组蛋白周转区域与心脏基因的顺式调控域相对应。有趣的是，染色质修饰物（包括多梳 EED[胚胎外胚层发育]）的募集与增强子处的组蛋白周转率呈正相关。从机制上讲，EED 通过直接与 BAF（BRG1[Brahma 相关基因 1]-相关因子）复合物相互作用，并利用游离组蛋白库中的核小体交换来进行标准化的组蛋白修饰，从而增加组蛋白周转，以抑制增强子的过度激活。
我们提出了一个模型，即复制独立的组蛋白周转加强了成年组织稳态中局部染色质状态的稳健性。
