title: Influence of ATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells.
abstract: Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM-deficient iPSCs relative to wild-type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral (RV) reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DDR reveals unique vulnerability of early replicating open chromatin to RV vectors.
authors.affiliation: 1 Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Junjie
authors.initials: J
authors.lastname: Lu
authors.affiliation: 2 Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine , Mayo Clinic, Rochester, Minnesota.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: 1 Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Baccei
authors.affiliation: 3 Department of Biological Sciences, Florida State University , Tallahassee, Florida.
authors.forename: Takayo
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: 3 Department of Biological Sciences, Florida State University , Tallahassee, Florida.
authors.forename: David M
authors.initials: DM
authors.lastname: Gilbert
authors.affiliation: 1 Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts.|4 Division of Neonatology, Department of Pediatrics, Massachusetts General Hospital , Boston, Massachusetts.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lerou
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000378:metabolism; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D004261:DNA Replication / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins