Dynamic interactions and cooperative functions of PGC-1alpha and MED1 in TRalpha-mediated activation of the brown-fat-specific UCP-1 gene

Mol Cell. 2009 Sep 24;35(6):755-68. doi: 10.1016/j.molcel.2009.09.015.

Abstract

PGC-1alpha is an inducible nuclear receptor coactivator with direct functions in both p300-mediated chromatin remodeling and Mediator-dependent transcription in vitro. Here, we have employed the PPARgamma- and TRalpha-activated brown adipose tissue-specific UCP-1 enhancer to investigate mechanistic aspects of PGC-1alpha function. We first demonstrate a cellular role for the PGC-1alpha-interacting MED1 subunit of Mediator in UCP-1 induction, as well as the accumulation of TRalpha, PPARgamma, PGC-1alpha, and MED1 on the UCP-1 enhancer in brown adipocytes. We then use biochemical assays to show that (i) PGC-1alpha is recruited to the TRalpha-RXRalpha-UCP-1 enhancer complex through interaction of an N-terminal LXXLL domain with TRalpha, (ii) MED1/Mediator displaces PGC-1alpha from TRalpha through LXXLL domain competition, and (iii) upon loss of PGC-1alpha-TRalpha interactions, PGC-1alpha remains associated with the enhancer complex through an interaction between PGC-1alpha and MED1 C-terminal domains. These results indicate dynamic MED1-dependent PGC-1alpha interactions related to functions in both chromatin remodeling and the transition to subsequent transcription initiation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cells, Cultured
  • Chromatin Assembly and Disassembly
  • Enhancer Elements, Genetic
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Ligands
  • Mediator Complex Subunit 1
  • Mice
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Retinoid X Receptor alpha / metabolism
  • Thyroid Hormone Receptors alpha / genetics
  • Thyroid Hormone Receptors alpha / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation*
  • Transfection
  • Uncoupling Protein 1
  • Up-Regulation

Substances

  • Ion Channels
  • Ligands
  • Med1 protein, mouse
  • Mediator Complex Subunit 1
  • Mitochondrial Proteins
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • Retinoid X Receptor alpha
  • Thyroid Hormone Receptors alpha
  • Trans-Activators
  • Transcription Factors
  • Ucp1 protein, mouse
  • Uncoupling Protein 1