Epigenetics, Liver Development, and Cancer

Decoding the contribution of DNA methylation to hepatocyte proliferation during liver development and in the regulation of liver cancer.
Decoding the contribution of DNA methylation to hepatocyte proliferation during liver development and in the regulation of liver cancer.

Epigenetic modifications underlie widespread changes in gene expression and alter chromatin structure, driving major biological events including cell division and differentiation. Hepatocytes are unique in that they are among the few differentiated cells that can proliferate. The epigenetic regulator, ubiquitin PhD and ring finger domain containing protein 1 (UHRF1) is required for DNA methylation and serves to coordinate multiple epigenetic marks.

Questions

1. How is epigenetic stress mitigated during development?

2. How does epigenetic damage lead to cancer?

3. How do methylome changes impact cell cycle progression?

Our discovery that Uhrf1, a master regulator of the epigenome, is essential for hepatocyte proliferation during liver regeneration and hepatic outgrowth during development suggests that epigenetic modifications mediated by Uhrf1 – primarily DNA methylation — are essential for hepatocyte division. We identified a requirement for Uhrf1 in zebrafish development and in liver regeneration. Moreover, we demonstrated that Uhrf1 is an oncogene in liver cancer.

Current work is focused on identifying the mechanisms by which Uhrf1 mediates methylome reprogramming during development, regeneration and cancer.