Human Hepatocyte Nuclear Factor 4-α encodes isoforms with distinct transcriptional functions

Abstract

HNF4 is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. In order to characterize the transcriptional capacities of all 12 HNF4 isoforms, stable lines expressing each isoform were generated. The entire transcriptome associated with each isoform was analyzed as well as their respective interacting proteome. Major differences were noted in the transcriptional function of these isoforms. The 1 and 2 isoforms were the most potent regulators of gene expression while the 3 isoform exhibited significantly reduced activity. The 4, 5 and 6 isoforms, which use an alternative first exon, were characterized for the first time, and showed a greatly reduced transcriptional potential with an inability to recognize the consensus response element of HNF4. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4 isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4 isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.