iPS cell generation-associated point mutations include many C > T substitutions via different cytosine modification
Ryoko Araki1,2, Tomo Suga3,4, Yuko Hoki3,4
1Stem Cell Biology Team, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan. araki.ryoko@qst.go.jp.
Nature Communications
|June 11, 2024
Summary
Genomic aberrations in induced pluripotent stem cells (iPSCs) pose safety risks. This study reveals that DNA demethylation during reprogramming may cause mutations, particularly at CpG sites.
Area of Science:
- Genomics
- Stem Cell Biology
- Epigenetics
Background:
- Genomic aberrations are a significant barrier to the safe clinical application of induced pluripotent stem cells (iPSCs).
- The origins and mechanisms driving these genomic alterations during iPSC generation are not fully understood.
Purpose of the Study:
- To investigate the de novo genomic mutations in human and mouse iPSC lines.
- To identify mutation-prone sites and understand the mechanisms underlying genomic instability during iPSC generation.
Main Methods:
- Whole-genome sequencing (WGS) analysis of human and mouse iPSC lines.
- Identification and characterization of mutation types and locations.
Main Results:
- Genomic mutations in iPSCs arise as de novo events.
- CpG sites, particularly within CpG islands (CGIs) and transcription start sites (TSSs), are mutation hotspots.
- Elevated mutations occur in retrotransposons, notably the AluY subfamily.
- Increased cytosine to thymine mutations are observed in differentially methylated regions.
Conclusions:
- Demethylation of methylated cytosine during genome reprogramming may be a mutagenic process in iPSC generation.
- Both cytosine deamination and demethylation contribute to genomic instability in iPSCs.
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