Author: ["Yuki Ohi","Han Qin","Chibo Hong","Laure Blouin","Jose M. Polo","Tingxia Guo","Zhongxia Qi","Sara L. Downey","Philip D. Manos","Derrick J. Rossi","Jingwei Yu","Matthias Hebrok","Konrad Hochedlinger","Joseph F. Costello","Jun S. Song","Miguel Ramalho-Santos"]
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Abstract
Human induced pluripotent stem (iPS) cells are remarkably similar to embryonic stem (ES) cells, but recent reports indicate that there may be important differences between them. We carried out a systematic comparison of human iPS cells generated from hepatocytes (representative of endoderm), skin fibroblasts (mesoderm) and melanocytes (ectoderm). All low-passage iPS cells analysed retain a transcriptional memory of the original cells. The persistent expression of somatic genes can be partially explained by incomplete promoter DNA methylation. This epigenetic mechanism underlies a robust form of memory that can be found in iPS cells generated by multiple laboratories using different methods, including RNA transfection. Incompletely silenced genes tend to be isolated from other genes that are repressed during reprogramming, indicating that recruitment of the silencing machinery may be inefficient at isolated genes. Knockdown of the incompletely reprogrammed gene C9orf64 (chromosome 9 open reading frame 64) reduces the efficiency of human iPS cell generation, indicating that somatic memory genes may be functionally relevant during reprogramming. A systematic comparison shows that differential DNA methylation accounts for some of the differences in somatic gene expression between induced pluripotent stem cells (iPSCs) and embryonic stem cells. The somatic genes that have persistent expression in iPSCs tend to be isolated from other genes that undergo silencing during reprogramming. This may explain the observed delay in recruitment of the DNA methylation machinery and in the genes being silenced.Cite this article
Ohi, Y., Qin, H., Hong, C. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 13, 541–549 (2011). https://doi.org/10.1038/ncb2239 