The conversion of somatic cells into pluripotent stem cells via overexpression of reprogramming factors involvesepigenetic remodeling. DNA methylation at a significant proportion of CpG sites in induced pluripotent st...The conversion of somatic cells into pluripotent stem cells via overexpression of reprogramming factors involvesepigenetic remodeling. DNA methylation at a significant proportion of CpG sites in induced pluripotent stem cells(iPSCs) differs from that of embryonic stem cells (ESCs). Whether different sets of reprogramming factors influencethe type and extent of aberrant DNA methylation in iPSCs differently remains unknown. In order to help resolvethis critical question, we generated human iPSCs from a common fibroblast cell source using either the Yamanakafactors (OCT4, SOX2, KLF4 and cMYC) or the Thomson factors (OCT4, SOX2, NANOG and LIN28), and determinedtheir genome-wide DNA methylation profiles. In addition to shared DNA methylation aberrations present in all ouriPSCs, we identified Yamanaka-iPSC (Y-iPSC)-specific and Thomson-iPSC (T-iPSC)-specific recurrent aberrations.Strikingly, not only were the genomic locations of the aberrations different but also their types: reprogrammingwith Yamanaka factors mainly resulted in failure to demethylate CpGs, whereas reprogramming with Thomsonfactors mainly resulted in failure to methylate CpGs. Differences in the level of transcripts encoding DNMT3b andTET3 between Y-iPSCs and T-iPSCs may contribute partially to the distinct types of aberrations. Finally, de novoaberrantly methylated genes in Y-iPSCs were enriched for NANOG targets that are also aberrantly methylated insome cancers. Our study thus reveals that the choice of reprogramming factors influences the amount, location,and class of DNA methylation aberrations in iPSCs. These findings may provide clues into how to produce humaniPSCs with fewer DNA methylation abnormalities.展开更多
基金NNB is supported by funding from the Ontario Institute for Cancer Research and DC is supported by funding from the Princess Margaret Cancer Foundation.
文摘The conversion of somatic cells into pluripotent stem cells via overexpression of reprogramming factors involvesepigenetic remodeling. DNA methylation at a significant proportion of CpG sites in induced pluripotent stem cells(iPSCs) differs from that of embryonic stem cells (ESCs). Whether different sets of reprogramming factors influencethe type and extent of aberrant DNA methylation in iPSCs differently remains unknown. In order to help resolvethis critical question, we generated human iPSCs from a common fibroblast cell source using either the Yamanakafactors (OCT4, SOX2, KLF4 and cMYC) or the Thomson factors (OCT4, SOX2, NANOG and LIN28), and determinedtheir genome-wide DNA methylation profiles. In addition to shared DNA methylation aberrations present in all ouriPSCs, we identified Yamanaka-iPSC (Y-iPSC)-specific and Thomson-iPSC (T-iPSC)-specific recurrent aberrations.Strikingly, not only were the genomic locations of the aberrations different but also their types: reprogrammingwith Yamanaka factors mainly resulted in failure to demethylate CpGs, whereas reprogramming with Thomsonfactors mainly resulted in failure to methylate CpGs. Differences in the level of transcripts encoding DNMT3b andTET3 between Y-iPSCs and T-iPSCs may contribute partially to the distinct types of aberrations. Finally, de novoaberrantly methylated genes in Y-iPSCs were enriched for NANOG targets that are also aberrantly methylated insome cancers. Our study thus reveals that the choice of reprogramming factors influences the amount, location,and class of DNA methylation aberrations in iPSCs. These findings may provide clues into how to produce humaniPSCs with fewer DNA methylation abnormalities.
