title: Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α.
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.
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Aguilo
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: SiDe
authors.initials: S
authors.lastname: Li
authors.affiliation: Children's Hospital Research Institute of Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Balasubramaniyan
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Sancho
authors.affiliation: 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.
authors.forename: Sabina
authors.initials: S
authors.lastname: Benko
authors.affiliation: Division of Nephrology, Department of Medicine, Laboratory of Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Biological Chemistry and Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vashisht
authors.affiliation: 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.
authors.forename: Madhumitha
authors.initials: M
authors.lastname: Rengasamy
authors.affiliation: 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.
authors.forename: Blanca
authors.initials: B
authors.lastname: Andino
authors.affiliation: 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.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Lin Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, PRC.
authors.forename: Chengmin
authors.initials: C
authors.lastname: Qian
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.affiliation: Department of Biological Chemistry and Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Division of Nephrology, Department of Medicine, Laboratory of Bioinformatics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Children's Hospital Research Institute of Colorado, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Suchy
authors.affiliation: 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.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D057809:HEK293 Cells; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010732:Phosphofructokinase-1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C542554:SIRT5 protein, mouse; D014157:Transcription Factors; D044503:5-Methylcytosine; D007521:Isocitrate Dehydrogenase; C000610956:isocitrate dehydrogenase 3, mouse; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D008780:Methyltransferases; C522860:Nsun7 protein, mouse; D010732:Phosphofructokinase-1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins