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

Francesca Aguilo, Si De Li, Natarajan Balasubramaniyan, Ana Sancho, Sabina Benko, Fan Zhang, Ajay Vashisht, Madhumitha Rengasamy, Blanca Andino, Chih hung Chen, Felix Zhou, Chengmin Qian, Ming Ming Zhou, James A. Wohlschlegel, Weijia Zhang, Frederick J. Suchy, Martin J. Walsh

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

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 m5C 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 m5C 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.

Original languageEnglish
Pages (from-to)479-492
Number of pages14
JournalCell Reports
Volume14
Issue number3
DOIs
StatePublished - 26 Jan 2016

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