Unraveling the Epigenetic Control of Hepatocyte-to-Bile Duct Cell Conversion

In 2012, it was discovered that hepatocytes in adult mice can undergo lineage conversion into cholangiocytes, or biliary epithelial cells. Since then, efforts have been made to elucidate the molecular mechanisms underlying this process, revealing the involvement of intracellular and extracellular signaling pathways. Additionally, changes in the chromatin structure of hepatocytes were observed, suggesting the involvement of epigenetic regulation. However, the causal relationship and detailed mechanisms remained unclear, partly due to the complexity of epigenetic regulation, which makes hypothesis-driven research challenging.

A research group led by Assistant Professor Takeshi Katsuda from the University of Tokyo, along with Professor Ben Stanger and graduate student Jonathan Sussman from the University of Pennsylvania, has elucidated part of the epigenetic regulatory mechanism underlying this phenomenon through a two-step in vivo screening. The team found that the distribution of various histone modifications changes during hepatocyte-to-cholangiocyte conversion. In particular, they identified that alterations in H3K36me2 distribution play a critical role, driven by two genes, Kdm2a and Nsd1. Furthermore, while disruptions in H3K36me2 distribution affect the efficiency of lineage conversion, the resulting changes in gene expression are minimal, and some cells still undergo lineage conversion similarly to normal conditions. These findings suggest that while epigenetics plays a crucial role in regulating lineage conversion, the process itself remains robust.

This study provides fundamental insights into the epigenetic regulation of lineage conversion. Future research could enable the directed conversion of hepatocytes into cholangiocytes, offering new therapeutic strategies for diseases associated with bile duct malformation, such as Alagille syndrome.

Papers
Journal: Genes & Development
Title: In vivo CRISPR screening reveals epigenetic regulators of hepatobiliary plasticity
Authors: Jonathan H. Sussman^#, Hector W. Cure, Salina Yuan, Kenji Ito, Irfan A. Asangani, Benjamin A Garcia, Ben Z. Stanger^*, Takeshi Katsuda^*,#
(#Co-first author; *Co-corresponding author)
DOI: 10.1101/gad.352420.124