p53 opposes Foxa1 in regulating chromatin modification and expression of the alpha‐fetoprotein gene during liver regeneration

Alpha‐fetoprotein (AFP) is highly expressed during fetal liver development but is rapidly repressed within a few weeks after birth. AFP is re‐expressed only during renewed cellular proliferation, as in liver regeneration and hepatocellular carcinoma. In order to assess chromatin structural alterations and the transcription factors that regulate and target these changes in chromatin and expression, we performed chromatin immunoprecipitation (ChIP) analysis of mouse liver tissue during development and at specific times during liver regeneration. In WT adult mouse liver, p53 binding to the AFP distal repressor correlates with silencing of AFP and de‐acetylation of AFP chromatin. p53‐null liver exhibits developmentally delayed AFP repression, suggesting that p53 plays a crucial role in regulation of AFP gene. At 2 h after 70% partial hepatectomy (PH), the level of p53 decreased while the transcription factor Foxa1 increased its binding at the overlapping p53/Foxa1 regulatory element in the AFP distal repressor region. At 36 h post‐PH, the level of Foxa1 was much higher than the level of p53. Concomitant with these alterations, we observed increased histone acetylation of AFP chromatin. Interestingly, at 48 h post‐PH, p53 began to re‐establish chromatin interaction at the distal repressor region and the ratio of bound p53 to Foxa1 increased. These data suggest a p53‐mediated mechanism for resetting repression of AFP after completion of liver regeneration, and highlight the opposing roles that p53 and Foxa1 play in regulating expression of the AFP gene by targeting alterations of chromatin structure.