title: DNA methylation dynamics in human induced pluripotent stem cells over time.
abstract: Epigenetic reprogramming is a critical event in the generation of induced pluripotent stem cells (iPSCs). Here, we determined the DNA methylation profiles of 22 human iPSC lines derived from five different cell types (human endometrium, placental artery endothelium, amnion, fetal lung fibroblast, and menstrual blood cell) and five human embryonic stem cell (ESC) lines, and we followed the aberrant methylation sites in iPSCs for up to 42 weeks. The iPSCs exhibited distinct epigenetic differences from ESCs, which were caused by aberrant methylation at early passages. Multiple appearances and then disappearances of random aberrant methylation were detected throughout iPSC reprogramming. Continuous passaging of the iPSCs diminished the differences between iPSCs and ESCs, implying that iPSCs lose the characteristics inherited from the parent cells and adapt to very closely resemble ESCs over time. Human iPSCs were gradually reprogrammed through the "convergence" of aberrant hyper-methylation events that continuously appeared in a de novo manner. This iPS reprogramming consisted of stochastic de novo methylation and selection/fixation of methylation in an environment suitable for ESCs. Taken together, random methylation and convergence are driving forces for long-term reprogramming of iPSCs to ESCs.
authors.affiliation: Department of Reproductive Biology, National Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nishino
authors.forename: Masashi
authors.initials: M
authors.lastname: Toyoda
authors.forename: Mayu
authors.initials: M
authors.lastname: Yamazaki-Inoue
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukawatase
authors.forename: Emi
authors.initials: E
authors.lastname: Chikazawa
authors.forename: Hironari
authors.initials: H
authors.lastname: Sakaguchi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Akutsu
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D020868:Gene Silencing; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D007621:Karyotyping; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding; D019076:Transgenes
chemical_list: D005819:Genetic Markers; C498907:MEG3 non-coding RNA, human; D011506:Proteins; D062085:RNA, Long Noncoding