Xist Intron 1 Repression by Transcriptional‐Activator‐Like Effectors Designer Transcriptional Factor Improves Somatic Cell Reprogramming in Mice. (21st February 2019)

• Record Type: Journal Article
• Authors: Zhang, Jindun; Gao, Xuefei; Yang, Jian; Fan, Xiaoying; Wang, Wei; Liang, Yanfeng; Fan, Lihong; Han, Hongmei; Xu, Xiaorong; Tang, Fuchou; Bao, Siqin; Liu, Pentao; Li, Xihe
• Is Part Of: Stem cells. Volume 37:Number 5(2019)
• Page Start: 599
• Page End: 608
• Publication Date: 2019-02-21
• Subjects: Xist intron 1 -- Transcriptional‐activator‐like effectors designer transcriptional factors -- Mouse embryonic fibroblast reprogramming -- Induced pluripotent stem cells -- Somatic cell nuclear transfer; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2928
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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. Stem Cells 2019;37:599–608 Abstract : R6 binding to the Xist intron 1 caused substantially higher H3K9me3, followed by X chromosomes opening and the repression of X‐linked genes, which may directly or indirectly activate some pluripotent genes, and finally promote the induced pluripotent stem cell induction and the somatic cell nuclear transfer embryo development in vitro.