HRP2-DPF3a-BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription
HRP2-DPF3a-BAF complex coordinates histone modification and chromatin remodeling to regulate myogenic gene transcription
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HRP2-DPF3a-BAF 复合物协调组蛋白修饰和染色质重塑来调节肌源性基因转录
DOI：
10.1093/nar/gkaa441
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Zhang L.
中科院分区：
文献类型：
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作者：
Zhu X;Lan B;Yi X;He C;Dang L;Zhou X;Lu Y;Sun Y;Liu Z;Bai X;Zhang K;Li B;Li M. J;Chen Y;Zhang L.
组蛋白修饰和染色质重塑之间的功能串扰已经成为细胞命运决定过程中转录控制的关键调控模式，但其潜在机制尚未完全了解。在这里，我们发现了一个HRP 2-DPF 3a-BAF表观遗传途径，协调甲基化组蛋白H3赖氨酸36（H3 K36 me）和ATP依赖的染色质重塑，以调节染色质动力学和基因转录在肌分化。使用siRNA筛选靶向表观遗传修饰剂，我们确定肝癌衍生的生长因子相关蛋白2（HRP 2）作为肌生成的关键调节因子。小鼠中HRP 2的敲除导致肌肉再生受损。从机制上讲，通过其HIV整合酶结合结构域（IBD），HRP 2通过直接与BAF 45 c（DPF 3a）亚基相互作用与BRG 1/BRM相关因子（BAF）染色质重塑复合物相关联。通过其Pro-Trp-Trp-Pro（PWWP）结构域，HRP 2优先结合H3 K36 me 2。与生物化学研究一致，ChIP-seq分析表明，HRP 2与DPF 3a在整个基因组中共定位，并且HRP 2/DPF 3a向染色质的募集依赖于H3 K36 me 2。综合转录组学和顺式组学分析，加上ATAC-seq，揭示了HRP 2和DPF 3a通过招募BAF复合物的ATP酶亚基BRG 1来增加染色质可及性，从而激活生肌基因。两者合计，这些结果阐明了关键作用的HRP 2-DPF 3a-BAF复合物在表观遗传协调基因转录肌分化过程中。
Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we discover an HRP2–DPF3a–BAF epigenetic pathway that coordinates methylated histone H3 lysine 36 (H3K36me) and ATP-dependent chromatin remodeling to regulate chromatin dynamics and gene transcription during myogenic differentiation. Using siRNA screening targeting epigenetic modifiers, we identify hepatoma-derived growth factor-related protein 2 (HRP2) as a key regulator of myogenesis. Knockout of HRP2 in mice leads to impaired muscle regeneration. Mechanistically, through its HIV integrase binding domain (IBD), HRP2 associates with the BRG1/BRM-associated factor (BAF) chromatin remodeling complex by interacting directly with the BAF45c (DPF3a) subunit. Through its Pro-Trp-Trp-Pro (PWWP) domain, HRP2 preferentially binds to H3K36me2. Consistent with the biochemical studies, ChIP-seq analyses show that HRP2 colocalizes with DPF3a across the genome and that the recruitment of HRP2/DPF3a to chromatin is dependent on H3K36me2. Integrative transcriptomic and cistromic analyses, coupled with ATAC-seq, reveal that HRP2 and DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of BRG1, the ATPase subunit of the BAF complex. Taken together, these results illuminate a key role for the HRP2-DPF3a-BAF complex in the epigenetic coordination of gene transcription during myogenic differentiation.