A Homeostatic Arid1a-Dependent Permissive Chromatin State Licenses Hepatocyte Responsiveness to Liver-Injury-Associated YAP Signaling

• Published in: Cell stem cell 2019-07, Vol.25 (1), p.54-68.e5
• Main Authors: Li, Weiping, Yang, Liguang, He, Qiang, Hu, Chaobo, Zhu, Linying, Ma, Xiaolong, Ma, Xueyan, Bao, Shujie, Li, Lu, Chen, Yingying, Deng, Xing, Zhang, Xin, Cen, Jin, Zhang, Lei, Wang, Zhong, Xie, Wei-Fen, Li, Hong, Li, Yixue, Hui, Lijian
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - metabolism; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Arid1a; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Self Renewal; Chromatin - metabolism; Chromatin Assembly and Disassembly; Clustered Regularly Interspaced Short Palindromic Repeats; DNA-Binding Proteins - metabolism; hepatocyte competence; Hepatocytes - physiology; Hippo/Yap; Homeostasis; Induced Pluripotent Stem Cells - physiology; Liver Regeneration; Mice; Mice, Transgenic; permissive chromatin; Signal Transduction; Transcription Factors - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.06.008

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. [Display omitted] •Arid1a expression in hepatocytes promotes liver regeneration after periportal injuries•Arid1a endows a permissive chromatin state to liver-progenitor-like cell-enriched genes•Arid1a-dependent permissive chromatin defines responsiveness to regenerative signals In vivo cellular reprogramming after injury can regenerate injured tissue and restore function. Li et al. show that Arid1a regulates liver regeneration by promoting a permissive chromatin state in hepatocytes, which renders them competent to respond to injury-associated regenerative signals and facilitates expression of liver-progenitor-like cell genes.