title: Erosion of dosage compensation impacts human iPSC disease modeling.
abstract: Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an "erosion" of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease.
authors.affiliation: The Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Shila
authors.initials: S
authors.lastname: Mekhoubad
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.forename: A Sophie
authors.initials: AS
authors.lastname: de Boer
authors.forename: Evangelos
authors.initials: E
authors.lastname: Kiskinis
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D002478:Cells, Cultured; D041321:Chromosomes, Human, X / Q000235:genetics; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D005260:Female; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D007926:Lesch-Nyhan Syndrome / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008954:Models, Biological; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics
chemical_list: D006657:Histones; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA