title: The distribution of genomic variations in human iPSCs is related to replication-timing reorganization during reprogramming.
abstract: Cell-fate change involves significant genome reorganization, including changes in replication timing, but how these changes are related to genetic variation has not been examined. To study how a change in replication timing that occurs during reprogramming impacts the copy-number variation (CNV) landscape, we generated genome-wide replication-timing profiles of induced pluripotent stem cells (iPSCs) and their parental fibroblasts. A significant portion of the genome changes replication timing as a result of reprogramming, indicative of overall genome reorganization. We found that early- and late-replicating domains in iPSCs are differentially affected by copy-number gains and losses and that in particular, CNV gains accumulate in regions of the genome that change to earlier replication during the reprogramming process. This differential relationship was present irrespective of reprogramming method. Overall, our findings reveal a functional association between reorganization of replication timing and the CNV landscape that emerges during reprogramming.
authors.affiliation: Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Takayo
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Baccei
authors.affiliation: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Gilbert
authors.affiliation: Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.affiliation: Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: plerou@partners.org.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lerou
mesh_terms: D065150:Cellular Reprogramming / Q000235:genetics*; D056915:DNA Copy Number Variations; D004261:DNA Replication / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*