Document Type



Life Sciences | Medicine and Health Sciences


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 ES cells 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 due to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hES cells, we find iPS cells tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which display incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (~80%) with aberrant iPS-ES non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute the epigenetic variation of iPSCs and iPSC-hESC differences.


Nat Cell Biol. Author manuscript; available in PMC Apr 24, 2014.

Published in final edited form as: Nat Cell Biol. Jun 2013; 15(6): 700–711. Published online May 19, 2013. doi: 10.1038/ncb2748 PMCID: PMC3998089 NIHMSID: NIHMS495809