Proteomics

Dataset Information

1

Functions of the 12 different isoforms of the hepatocyte nuclear factor 4 alpha (HNF4α)


ABSTRACT: HNF4α is a nuclear receptor regulating the transcription of genes involved mainly in development, cell differentiation and metabolism. Opposite functions for the two classes of P1 and P2 isoforms of HNF4α have recently been highlighted. These classes include 12 variants of HNF4α that can be expressed by the use of two promoters and by alternative splicing. Until now, the characterization of this transcription factor has ignored this diversity and has remained confined to the study of a fraction of the isoforms. We therefore wanted to clarify the situation by specifically characterizing the transcriptional functions of the 12 isoforms of HNF4α. We have generated for this purpose stable lines expressing each isoform of HNF4α in HCT 116 cells. We analyzed the whole transcriptome associated with each isoform by sequencing RNA, as well as their proteome by a BioID approach coupled to quantitative mass spectrometry. We noted major differences in the transcriptional function of the 12 isoforms. The α4, α5 and α6 isoforms have been characterized for the first time, and show a greatly reduced transcriptional potential. We have shown that these isoforms are unable to recognize the consensus response element of HNF4α. The α1 and α2 isoforms are the most potent regulators of gene expression, while the α3 isoform exhibits significantly reduced activity. Several transcription factors and coregulators have been identified as potential specific partners for certain HFH4α isoforms. The IRF-2BP2 co-repressor interacts specifically with isoforms which include the long form of the F domain of HNF4α. This specific interaction could explain the large number of genes modulated negatively by α1 and α2 compared to α3. The analysis integrating the vast amount of transcriptomic and proteomic data allows the identification of transcriptional regulatory mechanisms specific to certain isoforms, demonstrating the importance of considering all isoforms which can have diverse functions.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo sapiens  

TISSUE(S): Cell Culture, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Francois-Michel Boisvert  

LAB HEAD: Francois-Michel Boisvert

PROVIDER: PXD012146 | Pride | 2020-04-17

REPOSITORIES: pride

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Publications

Human Hepatocyte Nuclear Factor 4-α Encodes Isoforms with Distinct Transcriptional Functions.

Lambert Élie É   Babeu Jean-Philippe JP   Simoneau Joël J   Raisch Jennifer J   Lavergne Laurie L   Lévesque Dominique D   Jolibois Émilie É   Avino Mariano M   Scott Michelle S MS   Boudreau François F   Boisvert Francois-Michel FM  

Molecular & cellular proteomics : MCP 20200302 5


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 t  ...[more]

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