TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation

Daniil Alpern; Diana Langer; Benoit Ballester; Stephanie Le Gras; Christophe Romier; Gabrielle Mengus; Irwin Davidson

doi:10.7554/eLife.03613

TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation

Elife. 2014 Sep 10:3:e03613. doi: 10.7554/eLife.03613.

Authors

Daniil Alpern¹, Diana Langer¹, Benoit Ballester², Stephanie Le Gras¹, Christophe Romier³, Gabrielle Mengus¹, Irwin Davidson¹

Affiliations

¹ Department of Functional Genomics and Cancer, Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/UDS, Illkirch, France.
² Laboratoire TAGC, Aix-Marseille Université, UMR1090, Marseille, France.
³ Department of Integrated Structural Biology, Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/UDS, Illkirch, France.

Abstract

The functions of the TAF subunits of mammalian TFIID in physiological processes remain poorly characterised. In this study, we describe a novel function of TAFs in directing genomic occupancy of a transcriptional activator. Using liver-specific inactivation in mice, we show that the TAF4 subunit of TFIID is required for post-natal hepatocyte maturation. TAF4 promotes pre-initiation complex (PIC) formation at post-natal expressed liver function genes and down-regulates a subset of embryonic expressed genes by increased RNA polymerase II pausing. The TAF4-TAF12 heterodimer interacts directly with HNF4A and in vivo TAF4 is necessary to maintain HNF4A-directed embryonic gene expression at post-natal stages and promotes HNF4A occupancy of functional cis-regulatory elements adjacent to the transcription start sites of post-natal expressed genes. Stable HNF4A occupancy of these regulatory elements requires TAF4-dependent PIC formation highlighting that these are mutually dependent events. Local promoter-proximal HNF4A-TFIID interactions therefore act as instructive signals for post-natal hepatocyte differentiation.

Keywords: biochemistry; bioinformatics; chromosomes; developmental biology; genes; genomics; mouse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Bile Ducts / metabolism
Bile Ducts / pathology
Cell Communication
Cell Differentiation / genetics*
Cholestasis / complications
Cholestasis / metabolism
Cholestasis / pathology
Down-Regulation / genetics
Genome
Hepatocyte Nuclear Factor 4 / chemistry
Hepatocyte Nuclear Factor 4 / metabolism*
Hepatocytes / cytology*
Hepatocytes / metabolism*
Homeodomain Proteins / metabolism
Hypoglycemia / complications
Hypoglycemia / pathology
Mice
Mutation / genetics
Promoter Regions, Genetic*
Protein Binding / genetics
Protein Multimerization
Protein Structure, Tertiary
Protein Subunits / metabolism*
RNA Polymerase II / metabolism
TATA-Binding Protein Associated Factors
TATA-Box Binding Protein / metabolism
Transcription Factor TFIID / deficiency
Transcription Factor TFIID / metabolism*
Up-Regulation / genetics

Substances

Hepatocyte Nuclear Factor 4
Hnf4a protein, mouse
Homeodomain Proteins
Protein Subunits
TAF4 protein, mouse
TATA-Binding Protein Associated Factors
TATA-Box Binding Protein
Taf3 protein, mouse
Transcription Factor TFIID
RNA Polymerase II

Associated data

Dryad/10.5061/dryad.62GJ0
GEO/GSE57814

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.