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
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Research Support, N.I.H., Extramural
MeSH terms
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Adipose Tissue, Brown / metabolism*
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Animals
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Binding Sites
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Binding, Competitive
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Cells, Cultured
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Chromatin Assembly and Disassembly
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Enhancer Elements, Genetic
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Ion Channels / genetics
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Ion Channels / metabolism*
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Ligands
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Mediator Complex Subunit 1
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Mice
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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PPAR gamma / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Protein Structure, Tertiary
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RNA, Messenger / metabolism
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Retinoid X Receptor alpha / metabolism
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Thyroid Hormone Receptors alpha / genetics
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Thyroid Hormone Receptors alpha / metabolism*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation*
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Transfection
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Uncoupling Protein 1
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Up-Regulation
Substances
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Ion Channels
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Ligands
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Med1 protein, mouse
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Mediator Complex Subunit 1
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Mitochondrial Proteins
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PPAR gamma
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA, Messenger
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Retinoid X Receptor alpha
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Thyroid Hormone Receptors alpha
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Trans-Activators
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Transcription Factors
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Ucp1 protein, mouse
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Uncoupling Protein 1