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.

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

Grant support

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