title: Initiation and maintenance of pluripotency gene expression in the absence of cohesin.
abstract: Cohesin is implicated in establishing and maintaining pluripotency. Whether this is because of essential cohesin functions in the cell cycle or in gene regulation is unknown. Here we tested cohesin's contribution to reprogramming in systems that reactivate the expression of pluripotency genes in the absence of proliferation (embryonic stem [ES] cell heterokaryons) or DNA replication (nuclear transfer). Contrary to expectations, cohesin depletion enhanced the ability of ES cells to initiate somatic cell reprogramming in heterokaryons. This was explained by increased c-Myc (Myc) expression in cohesin-depleted ES cells, which promoted DNA replication-dependent reprogramming of somatic fusion partners. In contrast, cohesin-depleted somatic cells were poorly reprogrammed in heterokaryons, due in part to defective DNA replication. Pluripotency gene induction was rescued by Myc, which restored DNA replication, and by nuclear transfer, where reprogramming does not require DNA replication. These results redefine cohesin's role in pluripotency and reveal a novel function for Myc in promoting the replication-dependent reprogramming of somatic nuclei.
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors.forename: Thais
authors.initials: T
authors.lastname: Lavagnolli
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors.forename: Preksha
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Wellcome Trust, Cancer Research UK Gurdon Institute, Cambridge CB2 1QN, United Kingdom;
authors.forename: Eva
authors.initials: E
authors.lastname: Hörmanseder
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors.forename: Hegias
authors.initials: H
authors.lastname: Mira-Bontenbal
authors.affiliation: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dharmalingam
authors.affiliation: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Wellcome Trust, Cancer Research UK Gurdon Institute, Cambridge CB2 1QN, United Kingdom; Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, United Kingdom.
authors.forename: John B
authors.initials: JB
authors.lastname: Gurdon
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom;
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 ONN, United Kingdom; matthias.merkenschlager@csc.mrc.ac.uk.
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D065150:Cellular Reprogramming / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014981:Xenopus; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D016271:Proto-Oncogene Proteins c-myc; D000097722:Cohesins; C489428:Myc protein, mouse
keywords: cohesin; embryonic stem cells; heterokaryon; nuclear transfer; pluripotency; reprogramming