title: ERRs Mediate a Metabolic Switch Required for Somatic Cell Reprogramming to Pluripotency.
abstract: Cell metabolism is adaptive to extrinsic demands; however, the intrinsic metabolic demands that drive the induced pluripotent stem cell (iPSC) program remain unclear. Although glycolysis increases throughout the reprogramming process, we show that the estrogen-related nuclear receptors (ERRα and ERRγ) and their partnered co-factors PGC-1α and PGC-1β are transiently induced at an early stage, resulting in a burst of oxidative phosphorylation (OXPHOS) activity. Upregulation of ERRα or ERRγ is required for the OXPHOS burst in both human and mouse cells, respectively, as well as iPSC generation itself. Failure to induce this metabolic switch collapses the reprogramming process. Furthermore, we identify a rare pool of Sca1(-)/CD34(-) sortable cells that is highly enriched in bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors are ERRγ and PGC-1β positive and have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic gate prior to establishment of induced pluripotency.
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba 305-8562, Japan.
authors: Yasuyuki S
authors: YS
authors: Kida
authors: Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan; Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Shiga 525-8577, Japan.
authors: Teruhisa
authors: T
authors: Kawamura
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Zong
authors: Z
authors: Wei
authors: Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan.
authors: Takahiro
authors: T
authors: Sogo
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Sandra
authors: S
authors: Jacinto
authors: Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan; Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Shiga 525-8577, Japan.
authors: Asako
authors: A
authors: Shigeno
authors: Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba 305-8562, Japan.
authors: Hiroko
authors: H
authors: Kushige
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Eiji
authors: E
authors: Yoshihara
authors: Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
authors: Christopher
authors: C
authors: Liddle
authors: Genomic Analysis Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Joseph R
authors: JR
authors: Ecker
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Ruth T
authors: RT
authors: Yu
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Annette R
authors: AR
authors: Atkins
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Michael
authors: M
authors: Downes
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.
authors: Ronald M
authors: RM
authors: Evans
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000067696:Ataxin-1 / Q000378:metabolism; D002460:Cell Line; D065150:Cellular Reprogramming; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D039904:Pluripotent Stem Cells / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D018952:Antigens, CD34; D000067696:Ataxin-1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C490916:Esrrg protein, mouse; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse