Abstract
Induced pluripotent stem cells (iPSCs) are generated by direct reprogramming of somatic cells and hold great promise for novel therapies. However, several studies have reported genetic variations in iPSC genomes. Here, we investigated point mutations identified by whole-genome sequencing in mouse and human iPSCs in the context of epigenetic status. In contrast to disease-causing single-nucleotide polymorphisms, de novo point mutations introduced during reprogramming were underrepresented in protein-coding genes and in open chromatin regions, including transcription factor binding sites. Instead, these mutations occurred preferentially in structurally condensed lamina-associated heterochromatic domains, suggesting that chromatin organization is a factor that can bias the regional mutation rate in iPSC genomes. Mutation signature analysis implicated oxidative stress associated with reprogramming as a likely cause of point mutations. Altogether, our study provides deeper understanding of the mutational landscape of iPSC genomes, paving an important way toward the translation of iPSC-based cell therapy.
Highlights
Cancer genomics studies (Polak et al, 2015; Schuster-Bockler and Lehner, 2012; Zheng et al, 2014) revealed that the human somatic cell mutation rate is strongly influenced by epigenetic properties such as chromatin organization
We investigated the structural features of de novo point mutations identified by whole-genome sequencing (WGS) in the genomes of mouse and human Induced pluripotent stem cells (iPSCs)
De Novo Point Mutations in Mouse iPSCs Are Overrepresented in Intergenic Regions To examine the features of de novo point mutations identified by WGS, we integrated the mutation profiles in iPSCs with functional genomics data, including chromatin immunoprecipitation sequencing (ChIP-seq)
Summary
Cancer genomics studies (Polak et al, 2015; Schuster-Bockler and Lehner, 2012; Zheng et al, 2014) revealed that the human somatic cell mutation rate is strongly influenced by epigenetic properties such as chromatin organization. The present study provides better characterization of iPSC mutations at the whole-genome level and accelerates the translation of iPSC-based therapies
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.