Influence of ATM-mediated DNA damage response on genomic variation in human induced pluripotent stem cells

Junjie Lu, Hu Li, Anna Baccei, Takayo Sasaki, David M. Gilbert, Paul H. Lerou

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)740-747
Number of pages8
JournalStem Cells and Development
Volume25
Issue number9
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

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