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Cell Rep. 2016 Jan 26;14(3):479-492. doi: 10.1016/j.celrep.2015.12.043. Epub 2016 Jan 7.

Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α.

Author information

1
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Children's Hospital Research Institute of Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA.
4
Division of Nephrology, Department of Medicine, Laboratory of Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Department of Biological Chemistry and Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Biochemistry, Lin Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, PRC.
8
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: martin.walsh@mssm.edu.

Abstract

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

PMID:
26774474
PMCID:
PMC4731243
DOI:
10.1016/j.celrep.2015.12.043
[Indexed for MEDLINE]
Free PMC Article

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