@article{705695f423004d048ec1da7aadfee9cb,
title = "Aberrant DNA Methylation in Human iPSCs Associates with MYC-Binding Motifs in a Clone-Specific Manner Independent of Genetics",
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",
author = "Panopoulos, {Athanasia D.} and Smith, {Erin N.} and Arias, {Angelo D.} and Shepard, {Peter J.} and Yuriko Hishida and Veronica Modesto and Diffenderfer, {Kenneth E.} and Clay Conner and William Biggs and Efren Sandoval and Agnieszka D'Antonio-Chronowska and Berggren, {W. Travis} and {Izpisua Belmonte}, {Juan Carlos} and Frazer, {Kelly A.}",
note = "Funding Information: This work was supported in part by a CIRM grant GC1R-06673 (to K.A.F.) and NIH grants HG008118-01 (to K.A.F.), HL107442-05 (to K.A.F. and J.C.I.B.), DK105541 (to K.A.F.), DK112155 (to K.A.F.), and EY021237 (to K.A.F.). Work in the laboratory of J.C.I.B. was supported by grants from The Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002), Universidad Catolica San Antonio de Murcia (UCAM), and the G. Harold and Leila Y. Mathers Charitable Foundation. We thank the Gallagher family for their generous gift to the University of Notre Dame to support stem cell research. Methylation array data were generated at the UCSD IGM Genomics Center with support from NIH grant P30CA023100. We thank Dr. Roy Williams for CNV calling with Nexus software and Hiroko Matsui for processing array data. We would also like to thank Fangwen Rao and Dr. Daniel T. O'Conner for providing us with twin samples from the University of California San Diego Twins cohort. We dedicate this work to the memory of our dear colleague Dr. O'Conner. Efren Sandoval was an employee of Human Longevity, Inc. during the study and is now an employee of Helix. William Biggs is an employee of Human Longevity, Inc. Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = apr,
day = "6",
doi = "10.1016/j.stem.2017.03.010",
language = "English (US)",
volume = "20",
pages = "505--517.e6",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "4",
}