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Hepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor expressed in many cell types, including pancreatic β-cells. Mutations in the  HNF4α  gene in humans give rise to maturity-onset diabetes of the young (MODY1) characterized by defective insulin secretion by β-cells. To elucidate the mechanism underlying this disease, we introduced the splice form HNF4α2 or HNF4α8 into the rat β-cell line INS-1. Upon tetracycline-induced expression, both HNF4α isoforms caused distinct changes in cell morphology and a massive loss of cell numbers that was correlated with reduced proliferation and induced apoptosis. This differential activity was reflected in oligonucleotide microarray analysis that identified more genes affected by HNF4α2 compared to HNF4α8, and suggests that both isoforms regulate largely the same set of genes, with HNF4α2 being a stronger transactivator. We verified the induction of selected transcripts by real-time RT-PCR, including KAI1 and AIF, both known to have apoptotic potential. By establishing cell lines with inducible expression of these target genes, we deduce that both factors are insufficient to induce apoptosis. We propose that the anti-proliferative and apoptotic properties of HNF4α may be an essential feature impaired in MODY1 and possibly also in type 2 diabetes.

Tissue-specific transcription factor HNF4α inhibits cell proliferation and induces apoptosis in the pancreatic INS-1 β-cell line