Journal
STEM CELLS
Volume 37, Issue 5, Pages 599-608Publisher
OXFORD UNIV PRESS
DOI: 10.1002/stem.2928
Keywords
Xist intron 1; Transcriptional-activator-like effectors designer transcriptional factors; Mouse embryonic fibroblast reprogramming; Induced pluripotent stem cells; Somatic cell nuclear transfer
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Funding
- Ministry of Science and Technology project of Inner Mongolia [20130216]
- National Natural Science Foundation of China [31560335]
- Wellcome Trust [098051]
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Xist is the master regulator of X chromosome inactivation. In order to further understand the Xist locus in the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) and in somatic cell nuclear transfer (SCNT), we tested transcription-activator-like effectors-based designer transcriptional factors (dTFs), which were specific to numerous regions at the Xist locus. We report that the selected dTF repressor 6 (R6) binding the intron 1 of Xist, which caused higher H3K9me3 followed by X chromosome opening and repression of X-linked genes in mouse embryonic fibroblasts, rather than affecting Xist expression, substantially improved the iPSC generation and the SCNT preimplantation embryo development. Conversely, the dTF activator targeting the same genomic region of R6 decreased iPSC formation and blocked SCNT-embryo development. These results thus uncover the critical requirement for the Xist locus in epigenetic resetting, which is not directly related to Xist transcription. This may provide a unique route to improving the reprogramming.
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