title: Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity.
abstract: Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA-sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ∼50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele-specific expression show that iPSCs retain a donor-specific gene expression pattern. Network, pathway, and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Carcamo-Orive
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: Hoffman
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Cundiff
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Noam D
authors.initials: ND
authors.lastname: Beckmann
authors.affiliation: Department of Developmental and Regenerative Biology, Experimental Therapeutics Institute, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Sunita L
authors.initials: SL
authors.lastname: D'Souza
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Achchhe
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Skolkovo Institute of Science and Technology, Nobel Street, Building 3, Moscow 143026, Russia.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Papatsenko
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Fahim
authors.initials: F
authors.lastname: Abbasi
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Reaven
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94148, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Whalen
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahbazi
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Marc Y R
authors.initials: MYR
authors.lastname: Henrion
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Kuixi
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education, and Clinical Center (VISN 3), James J. Peters VA Medical Center, Bronx, NY 10468, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Pandey
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: rui.r.chang@mssm.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Chang
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: tomq1@stanford.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ihor
authors.initials: I
authors.lastname: Lemischka
mesh_terms: D000483:Alleles; D001499:Bayes Theorem; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D015203:Reproducibility of Results; D014158:Transcription, Genetic
chemical_list: D063146:Polycomb-Group Proteins
keywords: Polycomb targets; allelic imbalance; differentiation variability; eQTL; iPSC library; key drivers; network analysis; transcriptional variability; variance partition