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

Abstract

The nuclear receptor hepatocyte nuclear factor (HNF) 4 alpha is involved in a transcriptional network and plays an important role in pancreatic beta-cells. Mutations in the HNF4 alpha gene are correlated with maturity-onset diabetes of the young 1. HNF4 alpha isoforms result from both alternative splicing and alternate usage of promoters P1 and P2. It has recently been reported that HNF4 alpha 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 beta-cells and in the pancreatic beta-cell lines RIN m5F and HIT-T15. Expression of HNF4 alpha proteins originating from the P1 promoter was confirmed by immunodetection. Due to the presence of the activation function module AF-1, HNF4 alpha 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 alpha that is required for beta-cell function. Our results highlight that expression of P1 promoter-driven isoforms is important in the control of pancreatic beta-cell function.

Transcriptional networks controlling pancreatic development and beta cell function

“…What is remarkable about this mutation is that although Hnf1α regulates multiple genes in beta cells, the selective disruption of its regulation of Hnf4α has similar consequences to mutations that completely disrupt Hnf1α function [138]. On the other hand, this Hnf1 site mutation is one of three reported genetic defects that disrupt P2 promoter function and cause MODY [149,151], and together they provide compelling confirmation that this is the biologically significant Hnf4α promoter in the pancreas, despite the fact that P1-driven transcripts can be detected by PCR in human islet RNA [152] (S.F. Boj and J.…”

PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

“…This domain is indispensable for HNF4a function and its absence led to decrease in both the transcriptional potential and interaction with co-activators. [27][28][29][30] The Met49Val SNP may thus interfere with the function of HNF4a and influence the expression of genes involved with cell growth, immune function, amino acid metabolism, lipid and steroid metabolism, cell structure and function, some of which may possibly influence neutrophil recovery. More work is needed to validate the phenotypic associations of this SNP and to determine the functional effects in vitro.…”

Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4α (HNF4α) gene

“…The proximal P1 promoter drives the expression of the major isoforms in the adult hepatocyte, intestine and kidney (primarily HNF4α1 and HNF4α2); HNF4α2 differs from HNF4α1 by a 10 amino acid insertion in the C-terminal region (see Figure 1C). The distal P2 promoter drives the expression of isoforms present primarily in the embryonic liver and adult stomach and pancreas (primarily HNF4α7/8); HNF4α7/8 are 13 amino acids shorter than HNF4α1/2 due to a different N-terminus [16][17][18][19].…”