小柯机器人

代谢重编程调控初始多能干细胞中的DNA甲基化水平
2021-02-02 14:20

意大利帕多瓦大学Graziano Martello等研究人员合作发现,代谢重编程调控初始多能干细胞中的DNA甲基化水平。相关论文于2021年2月1日在线发表在《自然—遗传学》杂志上。

研究人员表示,在受精后,合子基因组会通过去甲基化来建立用于胚发育的空白蓝图。DNA甲基化发生在胞嘧啶的碳5(5mC)上,并被DNA甲基转移酶(Dnmt)催化。Tet(ten-eleven translocation)蛋白促进5mC氧化为羟甲基胞嘧啶(h5mC)。由Tet介导的其他氧化步骤导致h5mC转化为未修饰的胞嘧啶。Dnmt和Tet都在早期发育过程中动态表达,从而使得在胚胎着床前第3.5天(E3.5)的囊胚时期达到最低的5mC水平。

小鼠初始胚胎干细胞(ESC)来源于着床前的囊胚,并且仅在LIF(Jak–Stat通路的配体)与两种激酶GSK3和MEK抑制剂联合存在的情况下(2iLIF条件)表现出基因组低甲基化。相反,在带有LIF的胎牛血清培养基中培养的ESC显示出更高的DNA甲基化水平。 这些发现表明,LIF在血清存在的情况下不足以诱导基因组低甲基化。

研究人员发现,LIF–Stat3信号传导通过代谢重编程产生基因组低甲基化。Stat3-/-ESC显示出谷氨酰胺产生的α-酮戊二酸减少,从而导致Dnmt3a和Dnmt3b表达增加以及DNA甲基化。值得注意的是,通过线粒体中α-酮戊二酸可用性或Stat3激活的调控来动态控制基因组甲基化。α-酮戊二酸通过减少Otx2及其靶Dnmt3a和Dnmt3b的表达将代谢与表观基因组联系起来。即使没有活性LIF–Stat3,Otx2或Dnmt3a和Dnmt3b的基因失活也会导致基因组低甲基化。Stat3-/-ESC在印迹控制区域显示出甲基化增加和同源转录物表达改变。Stat3-/-胚胎的单细胞分析证实了Otx2、Dnmt3a和Dnmt3b以及印记基因的表达失调。几种癌症表现出Stat3过度激活和异常的DNA甲基化。因此,这些分子模块可能在病理条件下发挥功能。 

附:英文原文

Title: Metabolic control of DNA methylation in naive pluripotent cells

Author: Riccardo M. Betto, Linda Diamante, Valentina Perrera, Matteo Audano, Stefania Rapelli, Andrea Lauria, Danny Incarnato, Mattia Arboit, Silvia Pedretti, Giovanni Rigoni, Vincent Guerineau, David Touboul, Giuliano Giuseppe Stirparo, Tim Lohoff, Thorsten Boroviak, Paolo Grumati, Maria E. Soriano, Jennifer Nichols, Nico Mitro, Salvatore Oliviero, Graziano Martello

Issue&Volume: 2021-02-01

Abstract: Naive epiblast and embryonic stem cells (ESCs) give rise to all cells of adults. Such developmental plasticity is associated with genome hypomethylation. Here, we show that LIF–Stat3 signaling induces genomic hypomethylation via metabolic reconfiguration. Stat3/ ESCs show decreased α-ketoglutarate production from glutamine, leading to increased Dnmt3a and Dnmt3b expression and DNA methylation. Notably, genome methylation is dynamically controlled through modulation of α-ketoglutarate availability or Stat3 activation in mitochondria. Alpha-ketoglutarate links metabolism to the epigenome by reducing the expression of Otx2 and its targets Dnmt3a and Dnmt3b. Genetic inactivation of Otx2 or Dnmt3a and Dnmt3b results in genomic hypomethylation even in the absence of active LIF–Stat3. Stat3/ ESCs show increased methylation at imprinting control regions and altered expression of cognate transcripts. Single-cell analyses of Stat3/ embryos confirmed the dysregulated expression of Otx2, Dnmt3a and Dnmt3b as well as imprinted genes. Several cancers display Stat3 overactivation and abnormal DNA methylation; therefore, the molecular module that we describe might be exploited under pathological conditions.

DOI: 10.1038/s41588-020-00770-2

Source: https://www.nature.com/articles/s41588-020-00770-2

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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