title: Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency.
abstract: Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (~80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.forename: Keith E
authors.initials: KE
authors.lastname: Szulwach
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Xuekun
authors.initials: X
authors.lastname: Li
authors.forename: I-Ping
authors.initials: IP
authors.lastname: Chen
authors.forename: Ian S
authors.initials: IS
authors.lastname: Goldlust
authors.forename: Stormy J
authors.initials: SJ
authors.lastname: Chamberlain
authors.forename: Ann
authors.initials: A
authors.lastname: Dodd
authors.forename: He
authors.initials: H
authors.lastname: Gong
authors.forename: Gene
authors.initials: G
authors.lastname: Ananiev
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Han
authors.forename: Young-sup
authors.initials: YS
authors.lastname: Yoon
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Rudd
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
mesh_terms: D044503:5-Methylcytosine / Q000737:chemistry / Q000378:metabolism* / Q000031:analogs & derivatives; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000235:genetics; D053595:Embryonic Stem Cells; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D005347:Fibroblasts; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D006899:Mixed Function Oxygenases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C578792:TET3 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human