A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver injury-associated YAP signaling (ATAC-seq)

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 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. Normal hepatocytes and DDC-injured hepatocytes were isolated from Arid1a wild type and Arid1a liver specific KO mouse livers by a two-step liver collagenase perfusion and further purified by a series of low speed gravity centrifugation (3x2minx50g). DDC-injured hepatocytes were isolated from Sox9CreERT2:RFP reporter mice by gravity purification, and Sox9+ reprogrammed hepatocytes (LPLCs) were further isolated by sorting RFP+ hepatocytes based on the RFP expression via FACS. Biliary epithelia cells (BECs) were isolated from CK19CreERT2:RFP reporter mice by sorting RFP+ non parenchymal cells based on the RFP expression via FACS. The chromatin accessibility of normal hepatocytes, DDC-injured hepatocytes, LPLCs and BECs were identified via ATAC-seq. Please note that each processed data .bw file was generated from both replicate samples and is linked to the corresponding Rep1 sample records.