title: Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes.
abstract: 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.
authors: Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Montserrat C
authors: MC
authors: Anguera
authors: Ruslan
authors: R
authors: Sadreyev
authors: Zhaoqing
authors: Z
authors: Zhang
authors: Attila
authors: A
authors: Szanto
authors: Bernhard
authors: B
authors: Payer
authors: Steven D
authors: SD
authors: Sheridan
authors: Showming
authors: S
authors: Kwok
authors: Stephen J
authors: SJ
authors: Haggarty
authors: Mriganka
authors: M
authors: Sur
authors: Jason
authors: J
authors: Alvarez
authors: Alexander
authors: A
authors: Gimelbrant
authors: Maisam
authors: M
authors: Mitalipova
authors: James E
authors: JE
authors: Kirby
authors: Jeannie T
authors: JT
authors: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000494:pharmacology; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D049951:X Chromosome Inactivation / Q000187:drug effects / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA; D010100:Oxygen