title: PRDM16 enhances nuclear receptor-dependent transcription of the brown fat-specific Ucp1 gene through interactions with Mediator subunit MED1.
abstract: PR domain-containing 16 (PRDM16) induces expression of brown fat-specific genes in brown and beige adipocytes, although the underlying transcription-related mechanisms remain largely unknown. Here, in vitro studies show that PRDM16, through its zinc finger domains, directly interacts with the MED1 subunit of the Mediator complex, is recruited to the enhancer of the brown fat-specific uncoupling protein 1 (Ucp1) gene through this interaction, and enhances thyroid hormone receptor (TR)-driven transcription in a biochemically defined system in a Mediator-dependent manner, thus providing a direct link to the general transcription machinery. Complementary cell-based studies show that upon forskolin treatment, PRDM16 induces Ucp1 expression in undifferentiated murine embryonic fibroblasts, that this induction depends on MED1 and TR, and, consistent with a direct effect, that PRDM16 is recruited to the Ucp1 enhancer. Related studies have defined MED1 and PRDM16 interaction domains important for Ucp1 versus Ppargc1a induction by PRDM16. These results reveal novel mechanisms for PRDM16 function through the Mediator complex.
authors: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA;
authors: Satoshi
authors: S
authors: Iida
authors: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA;
authors: Wei
authors: W
authors: Chen
authors: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA;
authors: Tomoyoshi
authors: T
authors: Nakadai
authors: Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama 930-0194, Japan.
authors: Yoshiaki
authors: Y
authors: Ohkuma
authors: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA; roeder@rockefeller.edu.
authors: Robert G
authors: RG
authors: Roeder
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: D004268:DNA-Binding Proteins; D007473:Ion Channels; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D024101:Mitochondrial Proteins; C416371:PRDM16 protein, human; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005576:Colforsin
keywords: Mediator/MED1; PRDM16; Ucp1; brown/beige adipocytes; nuclear receptor; transcriptional regulation
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