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Cell Stem Cell. 2017 Apr 6;20(4):505-517.e6. doi: 10.1016/j.stem.2017.03.010.

Aberrant DNA Methylation in Human iPSCs Associates with MYC-Binding Motifs in a Clone-Specific Manner Independent of Genetics.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
2
Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093, USA.
3
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; BioSpyder Technologies, Inc., Carlsbad, CA 92008, USA.
4
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
5
Stem Cell Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
6
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
7
Human Longevity, Inc., San Diego, CA 92121, USA.
8
Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
9
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.
10
Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kafrazer@ucsd.edu.

Abstract

Induced pluripotent stem cells (iPSCs) show variable methylation patterns between lines, some of which reflect aberrant differences relative to embryonic stem cells (ESCs). To examine whether this aberrant methylation results from genetic variation or non-genetic mechanisms, we generated human iPSCs from monozygotic twins to investigate how genetic background, clone, and passage number contribute. We found that aberrantly methylated CpGs are enriched in regulatory regions associated with MYC protein motifs and affect gene expression. We classified differentially methylated CpGs as being associated with genetic and/or non-genetic factors (clone and passage), and we found that aberrant methylation preferentially occurs at CpGs associated with clone-specific effects. We further found that clone-specific effects play a strong role in recurrent aberrant methylation at specific CpG sites across different studies. Our results argue that a non-genetic biological mechanism underlies aberrant methylation in iPSCs and that it is likely based on a probabilistic process involving MYC that takes place during or shortly after reprogramming.

KEYWORDS:

MYC binding motifs; NHLBI NextGen; aberrant methylation; genetic background; iPSC; iPSCORE; induced pluripotent stem cells; methylation variation; reprogramming

PMID:
28388429
PMCID:
PMC5444384
DOI:
10.1016/j.stem.2017.03.010
[Indexed for MEDLINE]
Free PMC Article

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