De novo DNA methyltransferases DNMT3A and DNMT3B are essential for XIST silencing for erosion of dosage compensation in pluripotent stem cells.
De novo DNA methyltransferases DNMT3A and DNMT3B are essential for XIST silencing for erosion of dosage compensation in pluripotent stem cells.
复制标题
从头DNA甲基转移酶DNMT3A和DNMT3B对于XIST沉默以侵蚀多能干细胞中的剂量补偿是必需的。
DOI：
10.1016/j.stemcr.2021.07.015
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发表时间：
2021-09-14
影响因子：
5.9
通讯作者：
Eggan K
中科院分区：
文献类型：
--
作者：
Fukuda A;Hazelbaker DZ;Motosugi N;Hao J;Limone F;Beccard A;Mazzucato P;Messana A;Okada C;San Juan IG;Qian M;Umezawa A;Akutsu H;Barrett LE;Eggan K
人类多能干细胞（hPSC）已被证明是药物发现和基于细胞的疗法开发的有价值的工具。然而，对于X染色体失活的建立和维持至关重要的长非编码RNA XIST在培养期间被抑制，从而导致雌性hPSC中剂量补偿的侵蚀。在这里，我们报告说，从头DNA甲基转移酶DNMT 3A/3B是必要的XIST抑制在女性hPSC。我们发现，两个基因的缺失，而不是单个基因的缺失，抑制了XIST沉默，保持了H3 K27 me 3的异染色质标记，并且不会导致X连锁基因的整体过量。同时，XIST抑制后的DNMT 3A/3B缺失未能恢复X染色体失活。我们的研究结果表明，从头DNA甲基转移酶是负责启动女性hPSC中剂量补偿侵蚀的主要因素，并且XIST沉默以从头DNA甲基化非依赖性方式稳定维持。XIST表达与女性hPSC中启动子区域的DNA甲基化有关。新生DNA甲基转移酶DNMT 3A和DNMT 3B对XIST沉默至关重要。XIST沉默以新生DNA甲基化非依赖性方式维持。在这份报告中，Fukuda及其同事表明，新生DNA甲基转移酶DNMT 3A/3B对长非编码RNA XIST沉默至关重要，这在常规培养中是不可避免的，并导致女性人类多能干细胞中X染色体失活的剂量补偿的侵蚀。在XIST抑制之前删除这两种酶可以防止侵蚀的发生。
Human pluripotent stem cells (hPSCs) have proven to be valuable tools for both drug discovery and the development of cell-based therapies. However, the long non-coding RNA XIST, which is essential for the establishment and maintenance of X chromosome inactivation, is repressed during culture, thereby causing erosion of dosage compensation in female hPSCs. Here, we report that the de novo DNA methyltransferases DNMT3A/3B are necessary for XIST repression in female hPSCs. We found that the deletion of both genes, but not the individual genes, inhibited XIST silencing, maintained the heterochromatin mark of H3K27me3, and did not cause global overdosage in X-linked genes. Meanwhile, DNMT3A/3B deletion after XIST repression failed to restore X chromosome inactivation. Our findings revealed that de novo DNA methyltransferases are primary factors responsible for initiating erosion of dosage compensation in female hPSCs, and XIST silencing is stably maintained in a de novo DNA-methylation-independent manner. XIST expression is linked to DNA methylation at the promoter regions in female hPSCs De novo DNA methyltransferases DNMT3A and DNMT3B are essential for XIST silencing XIST silencing is maintained in a de novo DNA-methylation-independent manner In this report, Fukuda and colleagues show that the de novo DNA methyltransferases DNMT3A/3B are essential for long non-coding RNA XIST silencing, which is inevitable in conventional culture and causes the erosion of dosage compensation of X chromosome inactivation in female human pluripotent stem cells. Deletion of both enzymes prior to XIST repression can prevent the erosion from happening.
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影响因子：
11.8
作者：
Sangrithi MN;Royo H;Mahadevaiah SK;Ojarikre O;Bhaw L;Sesay A;Peters AH;Stadler M;Turner JM
通讯作者：
Turner JM
影响因子：
12.3
作者：
Robinson MD;Oshlack A
通讯作者：
Oshlack A
影响因子：
16.6
作者：
Makhlouf, Melanie;Ouimette, Jean-Francois;Oldfield, Andrew;Navarro, Pablo;Neuillet, Damien;Rougeulle, Claire
通讯作者：
Rougeulle, Claire
影响因子：
4.6
作者：
Fukuda A;Tanino M;Matoba R;Umezawa A;Akutsu H
通讯作者：
Akutsu H
影响因子：
2.9
作者：
Chapman, Andrew G.;Cotton, Allison M.;Brown, Carolyn J.
通讯作者：
Brown, Carolyn J.