Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation.

诱导多能干细胞（induced pluripotent stem cells，iPSCs）在再生医学以及疾病与发育研究领域具备极高的应用潜力。体细胞重编程涉及表观基因组重构，可使诱导多能干细胞获得与胚胎干细胞（embryonic stem cells，ES细胞）相似的特性。然而，目前仍不清楚在全基因组范围内，与胚胎干细胞类似的DNA甲基化模式的重建究竟能达到何种完备程度。本研究首次报道了5株人类诱导多能干细胞系中单碱基分辨率的全基因组DNA甲基化谱，并同步测定了胚胎干细胞、体细胞以及分化后的诱导多能干细胞与胚胎干细胞的甲基化组。诱导多能干细胞存在显著的重编程异质性，包括体细胞记忆与DNA甲基化的异常重编程。诱导多能干细胞在着丝粒与端粒附近共享兆碱基级别的差异甲基化区域，这类区域存在非CG甲基化重编程不完全、CG甲基化与组蛋白修饰存在差异等特征。最后，将诱导多能干细胞诱导分化为滋养层细胞的实验显示，CG甲基化重编程错误会以高频率传递至子代细胞，由此形成一种在分化后仍可稳定保留的诱导多能干细胞重编程特征标签。