Resetting transcription factor control circuitry toward ground-state pluripotency in human.
Resetting transcription factor control circuitry toward ground-state pluripotency in human.
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DOI：
10.1016/j.cell.2014.08.029
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发表时间：
2014-09-11
期刊：
影响因子：
64.5
通讯作者：
Smith A
中科院分区：
文献类型：
--
作者：
Takashima Y;Guo G;Loos R;Nichols J;Ficz G;Krueger F;Oxley D;Santos F;Clarke J;Mansfield W;Reik W;Bertone P;Smith A
目前的人类多能干细胞缺乏控制小鼠胚胎干细胞（ESC）基态的转录因子回路。在这里，我们报告说，两个组件的短期表达，NANOG和KLF2，足以点燃网络的其他元素，并重置人类多能状态。ERK和蛋白激酶C的抑制维持转基因独立的重新连接状态。重置细胞在没有ERK信号传导的情况下持续自我更新，表型稳定，并且核型完整。它们在体外分化并在体内形成畸胎瘤。如ESC中一样，代谢随着线粒体呼吸的激活而重新编程。DNA甲基化显著降低，转录组状态在多个细胞系中全局重新排列。基态转录因子TFCP2L1或KLF4的耗尽对常规人类多能干细胞具有边际影响，但会破坏重置状态。这些发现证明了在人类细胞中安装和传播基态多能性的功能控制电路的可行性。转录因子电路在人类多能干细胞中重新连接转录组和代谢与小鼠基态胚胎干细胞相似重置细胞中的全基因组低甲基化表明全局表观遗传擦除重置人类细胞可以并入小鼠植入前上胚层中，从而定义小鼠胚胎干细胞身份的转录因子电路将人类多能细胞转化为更幼稚的状态，其特征在于改变的转录和代谢活性、谱系引发的缺乏和整体DNA低甲基化。
Current human pluripotent stem cells lack the transcription factor circuitry that governs the ground state of mouse embryonic stem cells (ESC). Here, we report that short-term expression of two components, NANOG and KLF2, is sufficient to ignite other elements of the network and reset the human pluripotent state. Inhibition of ERK and protein kinase C sustains a transgene-independent rewired state. Reset cells self-renew continuously without ERK signaling, are phenotypically stable, and are karyotypically intact. They differentiate in vitro and form teratomas in vivo. Metabolism is reprogrammed with activation of mitochondrial respiration as in ESC. DNA methylation is dramatically reduced and transcriptome state is globally realigned across multiple cell lines. Depletion of ground-state transcription factors, TFCP2L1 or KLF4, has marginal impact on conventional human pluripotent stem cells but collapses the reset state. These findings demonstrate feasibility of installing and propagating functional control circuitry for ground-state pluripotency in human cells. Transcription factor circuitry is rewired in human pluripotent stem cells Transcriptome and metabolism are similar to mouse ground-state embryonic stem cells Genome-wide hypomethylation in reset cells indicates global epigenetic erasure Reset human cells can incorporate into mouse preimplantation epiblast Invoking the transcription factor circuitry that defines mouse embryonic stem cell identity converts human pluripotent cells to a more naive state, characterized by altered transcriptional and metabolic activity, absence of lineage priming, and global DNA hypomethylation.
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影响因子：
21.3
作者：
Boroviak T;Loos R;Bertone P;Smith A;Nichols J
通讯作者：
Nichols J
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Flicek P;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt S;Johnson N;Juettemann T;Kähäri AK;Keenan S;Kulesha E;Martin FJ;Maurel T;McLaren WM;Murphy DN;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ruffier M;Sheppard D;Taylor K;Thormann A;Trevanion SJ;Vullo A;Wilder SP;Wilson M;Zadissa A;Aken BL;Birney E;Cunningham F;Harrow J;Herrero J;Hubbard TJ;Kinsella R;Muffato M;Parker A;Spudich G;Yates A;Zerbino DR;Searle SM
通讯作者：
Searle SM
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
48
作者：
Engstrom, Par G.;Steijger, Tamara;Sipos, Botond;Grant, Gregory R.;Kahles, Andre;Raetsch, Gunnar;Goldman, Nick;Hubbard, Tim J.;Harrow, Jennifer;Guigo, Roderic;Bertone, Paul
通讯作者：
Bertone, Paul