The etiology of pediatric liver toxicity and ability of the liver to heal itself in the face of pediatric acute liver failure are unknown in many cases. To enlighten the potential contribution due to hepatocyte immaturity, our goal is to identify the mechanisms responsible for furthering the physiological functions and morphology of adult hepatocytes. During embryonic development until after birth, specified hepatocytes undergo a process of differentiation where they adopt the physiological functions and morphology associated with the adult liver. Our preliminary studies deleting the Zinc finger HIT-type containing 1 gene (Znhit1) at mid-gestation in embryonic hepatoblasts demonstrates a specific and essential role in the postnatal liver for survival, normal cellular architecture, and molecular gene signatures without changing the expression of the major hepatic master regulators. The goal of this application is to determine whether Znhit1 allows or disrupts access of transcription factors to different gene targets and/or enhancers, and thereby provides a switch towards hepatic cell differentiation.

We will determine whether Znhit1’s impact on liver function is due to 1) an autonomous hepatoblast and/or hepatocyte defect and 2) master regulator access to gene targets and/or enhancers. We will define what regulates the developmental switch for hepatocyte adult master regulator function.