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Hepatocyte Nuclear Factor 4 Isoforms Originated from the P1 Promoter Are Expressed in Human Pancreatic ß-Cells and Exhibit Stronger Transcriptional Potentials than P2 Promoter-Driven Isoforms

Institut National de la Santé et de la Recherche Médicale Unit 459 (J.E., E.M., P.F., B.L.); and Diabetes Cell Therapy Unit, ERIM 106 Institut National de la Santé et de la Recherche Médicale (T.B., B.L., F.P., J.K.-C., B.V.), Faculté H. Warembourg, Lille F 59045, France

Address all correspondence and requests for reprints to: B. Laine, Institut National de la Santé et de la Recherche Médicale Unit 459, Laboratoire de Biologie Cellulaire, Université H. Warembourg, 1 Place de Verdun, F 59045 Lille, France. E-mail: blaine{at}lille.inserm.fr.

The nuclear receptor hepatocyte nuclear factor (HNF) 4 is involved in a transcriptional network and plays an important role in pancreatic ß-cells. Mutations in the HNF4 gene are correlated with maturity-onset diabetes of the young 1. HNF4 isoforms result from both alternative splicing and alternate usage of promoters P1 and P2. It has recently been reported that HNF4 transcription is driven almost exclusively by the P2 promoter in pancreatic islets. We observed that transcripts from both P1 and P2 promoters were expressed in human pancreatic ß-cells and in the pancreatic ß-cell lines RIN m5F and HIT-T15. Expression of HNF4 proteins originating from the P1 promoter was confirmed by immunodetection. Due to the presence of the activation function module AF-1, HNF4 isoforms originating from the P1 promoter exhibit stronger transcriptional activities and recruit coactivators more efficiently than isoforms driven by the P2 promoter. Conversely, activities of isoforms produced by both promoters were similarly repressed by the corepressor small heterodimer partner. These behaviors were observed on the promoter of HNF1 that is required for ß-cell function. Our results highlight that expression of P1 promoter-driven isoforms is important in the control of pancreatic ß-cell function.

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