OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms.
OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms.
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DOI：
10.1073/pnas.2008890118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Nichols J
中科院分区：
文献类型：
--
作者：
Stirparo GG;Kurowski A;Yanagida A;Bates LE;Strawbridge SE;Hladkou S;Stuart HT;Boroviak TE;Silva JCR;Nichols J
我们使用单细胞全基因组转录谱分析和蛋白质定量来研究OCT 4在小鼠胚胎中建立多能性中的作用。令人惊讶的是，除了STAT 3信号通路的成员之外，大多数多能性相关因子在OCT 4无效早期囊胚中正常诱导。巧合的是，某些滋养外胚层标记物被诱导，但不包括Cdx 2，Cdx 2以前被认为在体外抑制Pou 5 f1。这种异位基因激活表明OCT 4在维持染色质处于多能性相容状态中的作用，可能通过UTF 1，一种已知的OCT 4靶标。在植入时，OCT 4无效内细胞团在形态上类似于滋养外胚层，但表现出将代谢和物理应激反应与OCT 4缺失联系起来的分子差异。这些作用与STAT 3信号传导减少和随后的氧化呼吸减少相关。OCT 4是体内和体外控制多能性的分子回路的基本组成部分。为了确定OCT 4如何在胚胎中建立和保护多能谱系，我们在两个发育阶段对对照和OCT 4无效囊胚内细胞团使用了比较单细胞转录组学和定量免疫荧光。令人惊讶的是，除了JAK/STAT信号机制外，早期小鼠胚胎中大多数多能性相关转录因子的激活独立于OCT 4发生。同时，OCT 4无效内细胞团异位激活滋养外胚层相关基因的子集。代谢途径的检查暗示OCT 4对限速糖酵解酶的调节，与维持糖酵解的作用一致。此外，在OCT 4无效胚胎中特异性检测到溶酶体途径的上调。这一发现暗示在正常滋养外胚层的产生中需要OCT 4。总的来说，我们的研究结果揭示了细胞代谢和生物物理特性的调节作为OCT 4指导多能性的机制。
We used single-cell whole-genome transcriptional profiling and protein quantification to investigate the role of OCT4 in establishing pluripotency in the murine embryo. Surprisingly, most pluripotency-associated factors are induced normally in OCT4 null early blastocysts, apart from members of the STAT3 signaling pathway. Coincidentally, certain trophectoderm markers are induced but not Cdx2, which was previously implicated to repress Pou5f1 in vitro. This ectopic gene activation suggests a role for OCT4 in maintaining chromatin in a pluripotency-compatible state, likely via UTF1, a known OCT4 target. At implantation, OCT4 null inner cell masses morphologically resemble trophectoderm but exhibit molecular differences linking metabolic and physical stress responses to loss of OCT4. These effects correlate with reduced STAT3 signaling and consequent reduction of oxidative respiration. OCT4 is a fundamental component of the molecular circuitry governing pluripotency in vivo and in vitro. To determine how OCT4 establishes and protects the pluripotent lineage in the embryo, we used comparative single-cell transcriptomics and quantitative immunofluorescence on control and OCT4 null blastocyst inner cell masses at two developmental stages. Surprisingly, activation of most pluripotency-associated transcription factors in the early mouse embryo occurs independently of OCT4, with the exception of the JAK/STAT signaling machinery. Concurrently, OCT4 null inner cell masses ectopically activate a subset of trophectoderm-associated genes. Inspection of metabolic pathways implicates the regulation of rate-limiting glycolytic enzymes by OCT4, consistent with a role in sustaining glycolysis. Furthermore, up-regulation of the lysosomal pathway was specifically detected in OCT4 null embryos. This finding implicates a requirement for OCT4 in the production of normal trophectoderm. Collectively, our findings uncover regulation of cellular metabolism and biophysical properties as mechanisms by which OCT4 instructs pluripotency.
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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
DOI：
10.1242/dev.167833
发表时间：
2018-11-09
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Boroviak T;Stirparo GG;Dietmann S;Hernando-Herraez I;Mohammed H;Reik W;Smith A;Sasaki E;Nichols J;Bertone P
通讯作者：
Bertone P
影响因子：
10.5
作者：
Brewer JR;Molotkov A;Mazot P;Hoch RV;Soriano P
通讯作者：
Soriano P
影响因子：
9.2
作者：
Hirate, Yoshikazu;Hirahara, Shino;Inoue, Ken-ichi;Suzuki, Atsushi;Alarcon, Vernadeth B.;Akimoto, Kazunori;Hirai, Takaaki;Hara, Takeshi;Adachi, Makoto;Chida, Kazuhiro;Ohno, Shigeo;Marikawa, Yusuke;Nakao, Kazuki;Shimono, Akihiko;Sasaki, Hiroshi
通讯作者：
Sasaki, Hiroshi