Journal Article

Incomplete DNA methylation underlies a transcriptional memory of the somatic cell in human iPS cells

Rossi, Derrick J., Hong, Chibo, Yu, Jingwei, Qi, Zhongxia, Ramalho-Santos, Miguel, Manos, Philip D., Guo, Tingxia, Qin, Han, Ohi, Yuki, Costello, Joseph F., Hochedlinger, Konrad, Blouin, Laure, Polo, Jose M., Hebrok, Matthias, Downey, Sara L., Song, Jun S.

2011

Overview

Human induced pluripotent stem (iPS) cells are remarkably similar to embryonic stem (ES) cells, but recent reports suggest that there may be important differences between them. We performed a systematic comparison of human iPS cells generated from hepatocytes (representative of endoderm), skin fibroblasts (mesoderm) and melanocytes (ectoderm). All low passage iPS cells analyzed 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 reduces the efficiency of human iPS cell generation, suggesting that somatic memory genes may be functionally relevant during reprogramming.