A YAP–TEAD4–CTCF transcriptional regulatory axis associated with the elimination of injured hepatocytes from the liver

The liver maintains tissue homeostasis both by undergoing regeneration and by eliminating abnormal or injured hepatocytes. The transcriptional coactivator YAP in collaboration with the TEAD family of transcription factors regulates hepatocyte proliferation. It has also been associated with injured hepatocyte elimination whereby YAP-active injured hepatocytes are extruded into the sinusoidal lumen, and undergo cell death followed by macrophage phagocytosis. However, the molecular mechanisms underlying this process are unknown. To address this, we performed RNA-seq analysis in YAP-active injured hepatocytes that are eliminated from the liver. We found increased expression of multiple genes associated with cell cycle arrest and cytoskeletal remodeling. Ligand–receptor analysis using single-cell spatial transcriptomics showed that YAP-active hepatocytes express the secreted factors CSF1 and CCL2, which promote macrophage recruitment and activation. ATAC-seq analysis in YAP-active hepatocytes revealed a significant increase in chromatin accessibility at regions containing CTCF-binding motifs, and the YAP–TEAD4 complex associated with CTCF in the nucleus. These results indicate that a YAP–TEAD4–CTCF axis shapes the gene expression program underlying injured hepatocyte elimination through chromatin structural remodeling, resulting in liver homeostasis.