title: ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.
abstract: Embryonic stem (ES) cells are in a dynamic equilibrium of distinct functional states, characterized by the heterogeneous expression of critical pluripotency factors and regulated by a spectrum of reversible histone modifications. Maintenance of this equilibrium is a hallmark of pluripotency. Here we find that the ADP-ribosyltransferases Parp1 and Parp7 play a critical role in safeguarding this state by occupying key pluripotency genes, notably Nanog, Pou5f1, Sox2, Stella, Tet1 and Zfp42, thereby protecting them from progressive epigenetic repression. In the absence of either Parp1 or Parp7, or upon inhibition of the ADP-ribosylating activity, ES cells exhibit a decrease in ground state pluripotency as they cannot maintain the typical heterogeneity characteristic of the metastable state. As a consequence, they display a higher propensity to differentiate. These findings place Parp1 and Parp7 at the genetic-epigenetic interface of pluripotency networks, fine-tuning the transcriptional heterogeneity and thereby determining the developmental plasticity of ES cells.
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Roper
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chrysanthou
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Senner
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Arnold
authors.initials: A
authors.lastname: Sienerth
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gnan
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Murray
authors.affiliation: Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Paulina
authors.initials: P
authors.lastname: Latos
authors.affiliation: Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK myriam.hemberger@babraham.ac.uk.
authors.forename: Myriam
authors.initials: M
authors.lastname: Hemberger
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology*; D008745:Methylation; D051379:Mice; D009154:Mutation; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000201:enzymology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C500759:Elf5 protein, mouse; D014157:Transcription Factors; D036002:ADP Ribose Transferases; C000592801:Parp7 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases