Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes

Cell Stem Cell. 2012 Jul 6;11(1):75-90. doi: 10.1016/j.stem.2012.03.008.


Although human induced pluripotent stem cells (hiPSCs) have enormous potential in regenerative medicine, their epigenetic variability suggests that some lines may not be suitable for human therapy. There are currently few benchmarks for assessing quality. Here we show that X-inactivation markers can be used to separate hiPSC lines into distinct epigenetic classes and that the classes are phenotypically distinct. Loss of XIST expression is strongly correlated with upregulation of X-linked oncogenes, accelerated growth rate in vitro, and poorer differentiation in vivo. Whereas differences in X-inactivation potential result in epigenetic variability of female hiPSC lines, male hiPSC lines generally resemble each other and do not overexpress the oncogenes. Neither physiological oxygen levels nor HDAC inhibitors offer advantages to culturing female hiPSC lines. We conclude that female hiPSCs may be epigenetically less stable in culture and caution that loss of XIST may result in qualitatively less desirable stem cell lines.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Proliferation / drug effects
  • Chromosomes, Human, X / genetics
  • Female
  • Gene Expression Profiling*
  • Genes, Neoplasm / genetics*
  • Genome, Human / genetics
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Mice
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Oligonucleotide Array Sequence Analysis
  • Oxygen / pharmacology
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism
  • Sex Characteristics*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • X Chromosome Inactivation / drug effects
  • X Chromosome Inactivation / genetics


  • Histone Deacetylase Inhibitors
  • RNA, Long Noncoding
  • RNA, Untranslated
  • XIST non-coding RNA
  • Oxygen