Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity

Ivan Carcamo-Orive, Gabriel E. Hoffman, Paige Cundiff, Noam D. Beckmann, Sunita L. D'Souza, Joshua W. Knowles, Achchhe Patel, Dimitri Papatsenko, Fahim Abbasi, Gerald M. Reaven, Sean Whalen, Philip Lee, Mohammad Shahbazi, Marc Y.R. Henrion, Kuixi Zhu, Sven Wang, Panos Roussos, Eric E. Schadt, Gaurav Pandey, Rui ChangThomas Quertermous, Ihor Lemischka

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)518-532.e9
JournalCell Stem Cell
Volume20
Issue number4
DOIs
StatePublished - Apr 6 2017
Externally publishedYes

Keywords

  • Polycomb targets
  • allelic imbalance
  • differentiation variability
  • eQTL
  • iPSC library
  • key drivers
  • network analysis
  • transcriptional variability
  • variance partition

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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