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Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency

 Tao Wang  ;  Hao Wu  ;  Yujing Li  ;  Keith E. Szulwach  ;  Li Lin  ;  Xuekun Li  ;  I-Ping Chen  ;  Ian S. Goldlust  ;  Stormy J. Chamberlain  ;  Ann Dodd  ;  He Gong  ;  Gene Ananiev  ;  Ji Woong Han  ;  Young-sup Yoon  ;  M. Katharine Rudd  ;  Miao Yu  ;  Chun-Xiao Song  ;  Chuan He  ;  Qiang Chang  ;  Stephen T. Warren  ;  Peng Jin 
 Nature Cell Biology, Vol.15(6) : 700-711, 2013 
Journal Title
 Nature Cell Biology 
Issue Date
5-Methylcytosine/chemistry ; 5-Methylcytosine/metabolism* ; Cell Differentiation ; Cell Line ; Cellular Reprogramming ; Cytosine/analogs & derivatives* ; Cytosine/metabolism ; DNA Methylation ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism* ; Dioxygenases/genetics ; Embryonic Stem Cells ; Enzyme Activation ; Epigenesis, Genetic ; Fibroblasts ; Humans ; Induced Pluripotent Stem Cells/metabolism* ; Mixed Function Oxygenases ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism* ; RNA Interference ; RNA, Small Interfering ; Sequence Alignment ; Transcription Factors/genetics ; Transcription Factors/metabolism
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.
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Yonsei Authors
Yoon, Young Sup(윤영섭)
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