Abstract
HNF4α is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. To characterize the transcriptional capacities of all 12 HNF4α 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 α1 and α2 isoforms were the strongest regulators of gene expression whereas the α3 isoform exhibited significantly reduced activity. The α4, α5, and α6 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 HNF4α. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4α isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4α isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.
Highlights
The entire transcriptome associated with each isoform were analyzed as well as their respective interacting proteome using BioID
The nomenclature surrounding the superfamily of Nuclear receptors (NR), based on their phylogeny, consists of six subfamilies comprised of several groups (Nuclear Receptors Nomenclature Committee, 1999)
HNF4␣ (Hepatocyte Nuclear Factor 4 alpha) is a transcription factor of the nuclear receptor family that was initially identified as a regulator of liver-specific gene expression [10, 11]
Summary
The A/B region, located at the N-terminal end, is highly variable between the various NR It typically contains an AF-1 transactivation region (Activation Function) which is active independently of ligand binding and allows the interaction of the receptor with various coregulators and other transcription factors [3]. In contrast to the AF-1 region, the activity of the AF-2 region is dependent on ligand binding to LBD This induces a conformational change in the LBD, generating a pocket that can interact with the LXXLL motif present on a host of transcriptional coactivators [8]. HNF4␣ has long been considered an orphan nuclear receptor, crystallography of the LBD initially revealed the presence of fatty acids of various compositions bound at the level of the ligand binding pocket of HNF4␣ [20]. Both RXR␣//␥ and RAR␣ nuclear receptors, known for their ability to form heterodimers with several NR, do not assemble into heterodimers with HNF4␣ [23, 24]
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