A Homeostatic Arid1a-Dependent Permissive Chromatin State Licenses Hepatocyte Responsiveness to Liver-Injury-Associated YAP Signaling
A Homeostatic Arid1a-Dependent Permissive Chromatin State Licenses Hepatocyte Responsiveness to Liver-Injury-Associated YAP Signaling
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稳态 Arid1a 依赖性许可染色质状态许可肝细胞对肝损伤相关 YAP 信号的反应
DOI：
10.1016/j.stem.2019.06.008
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发表时间：
2019-07-03
期刊：
影响因子：
23.9
通讯作者：
Hui, Lijian
中科院分区：
文献类型：
--
作者：
Li, Weiping;Yang, Liguang;Hui, Lijian
损伤后，分化的上皮细胞可以通过重编程为其他细胞类型，作为组织再生的干细胞非依赖性来源。分化细胞可塑性的内在分子基础在很大程度上仍然没有得到解决。在这里，我们表明，Arid 1a，SWI/SNF染色质重塑复合物的关键组成部分，控制肝再生和基因表达与损伤诱导的肝祖细胞样细胞（LPLC）的出现。肝细胞特异性Arid 1a消融减少了几种门静脉周围肝损伤模型中的LPLC基因表达，并损害肝再生，导致器官功能障碍。Arid 1a在稳态过程中在富含LPLC的基因处建立了允许的染色质状态，这表明它赋予肝细胞对损伤诱导的信号做出反应的能力。同样，Arid 1a促进雅普（一种关键的再生信号通路）与富含LPLC的基因的结合，Arid 1a缺失可防止损伤后YAP相关的诱导。总之，这些发现提供了一个框架，研究损伤诱导的LPLC的贡献，门静脉周围肝再生。
Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced liver-progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.