Grant: CIHR Fellowship

The death rate caused by hepatocellular carcinoma (HCC), the most common liver cancer, has been globally increasing over recent decades. However, current therapeutic options are limited due to the lack of knowledge about the underlying mechanisms of HCC. In many liver cancers, genes required for liver development are highly expressed, suggesting that embryonic cell programs are reactivated. Moreover, the gene encoding Lysine Methyl Transferase (KMT) 2D is often mutated in HCCs, affecting gene expression profiles by altering the genomic landscape. We discovered that KMT2D interacts with a liver transcription factor, Hepatocyte Nuclear Factor 4A (HNF4A), which has crucial roles in determining the fate of liver cells and developing HCC. Here, I propose to investigate the functional relationships of KMT2D and HNF4A in hepatocyte identity and HCC progression by carrying out multidisciplinary approaches, including cell biology, bioengineering, and epigenetics, that study reversible genome structural changes. I will use liver-like organoids derived from human pluripotent stem cells (hPSCs), closely mimicking human livers. I will reveal how loss- and gain-of-function for KMT2D change the genomic structure and alter gene expression essential for proper liver specification, development, and growth. My proposed research will help clarify the potential functional relationships between KMT2D and HNF4A in liver development and provide valuable information regarding the epigenetic etiology of life-threatening liver disease, HCC.