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

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1 alpha 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-1 alpha[K779me] with the Spt-AdaGcn5-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-1 alpha 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-1 alpha at the eRNA level to fine-tune energy metabolism.