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Hepatocyte nuclear factor 4 alpha (HNF4α) knockdown stimulates pro‐mitogenic gene expression in hepatocytes
Author(s) -
Walesky Chad Michael,
Gunewardena Sumedha,
Terwilliger Ernest F.,
Edwards Genea,
Wolfe Andy,
Apte Udayan
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.115.6
Subject(s) - gene knockdown , hepatocyte nuclear factor 4 , hepatocyte nuclear factors , hepatocyte , biology , cell growth , microbiology and biotechnology , gene expression , gene , cancer research , transcription factor , genetics , nuclear receptor , in vitro
HNF4α, the master regulator of hepatocyte differentiation, has been recently shown to inhibit hepatocyte proliferation via yet to be identified mechanisms. We investigated the mechanisms of HNF4α‐induced inhibition of hepatocyte proliferation using two novel HNF4α knockdown mouse models. HNF4α was deleted in adult livers using inducible cre‐lox technology. Deletion of HNF4α resulted in increased hepatocyte proliferation confirmed by PCNA staining. Comparative global gene expression analysis revealed a set of genes commonly regulated in both HNF4α deletion models. Majority of the down‐regulated genes were previously known HNF4α target genes involved in hepatic differentiation. Interestingly, majority of the 500+ up‐regulated genes were associated with cell proliferation and cancer. Real Time PCR analysis further confirmed up‐regulation of select genes including Egr‐1, various Cyclins, Aurora Kinase A, BIRC5, Cdc20, Cdca3, Ect2, Eid1, and Polo‐like Kinase 1. A combined gene expression‐ChIP‐seq analysis revealed a set of 32 HNF4α‐regulated pro‐mitogenic genes that are repressed in adult hepatocytes. Our data indicate that HNF4α inhibits hepatocyte proliferation by repression of specific pro‐mitogenic genes. These data highlight the role of HNF4α in regulation of hepatocyte proliferation with implications in liver homeostasis and cancer pathogenesis.