KANSL3 directs transcriptional programs essential for hepatic metabolism and differentiation [ChIP-seq]

Understanding the molecular mechanisms governing liver homeostasis and disease progression is essential for advancing therapeutic strategies for chronic liver diseases and hepatocellular carcinoma, with emerging evidence highlighting the pivotal role of epigenetic regulation in these progressive types of diseases. Here, we show that hepatic deletion of the epigenetic regulator KANSL3 initiates a series of pathological changes leading to early-onset chronic liver disease. The absence of KANSL3 leads to biliary hyperplasia and early hepatic fibrosis. We identify KANSL3 as a master regulator of core hepatocyte gene expression through its regulation of histone acetylation, which significantly alters transcriptional networks in the liver. Single-cell RNA sequencing (scRNA-seq) analysis of Kansl3 liver knockout (LKO) animals reveals a marked shift in liver cellular composition following Kansl3 depletion. We show that the hepatic epithelial cells of Kansl3 LKO mice and Kansl3-depleted ductal organoids exhibit impaired differentiation into mature hepatocytes, uncovering the importance of KANSL3 in hepatic cell fate decisions. Ultimately, chronic loss of KANSL3 induces significant changes in the liver microenvironment, promoting a premalignant state characterized by an immunosuppressive environment linked to hepatocellular carcinoma (HCC) progression. These results highlight KANSL3 as a crucial regulator of liver homeostasis and a promising target for drug discovery. Hepa1-6 experiment: H4K16ac level in Hepa 1-6 HA-dTAG-KANSL3 cells upon degradation of KANSL3. Hepa 1-6 HA-dTAG-KANSL3 cells were treated for 24hrs with either dTAG-NEG control compound or dTAG13 to rapidly degrade KANSL3. Wildtype liver experiment: Identification of KANSL3 binding targets and histone modifications in wildtype liver tissue.