L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation.
L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation.
复制标题
DOI：
10.1016/j.stemcr.2013.09.001
复制
发表时间：
2013
影响因子：
5.9
通讯作者：
Minchiotti, Gabriella
中科院分区：
文献类型：
--
作者：
Comes, Stefania;Gagliardi, Miriam;Laprano, Nicola;Fico, Annalisa;Cimmino, Amelia;Palamidessi, Andrea;De Cesare, Dario;De Falco, Sandro;Angelini, Claudia;Scita, Giorgio;Patriarca, Eduardo J.;Matarazzo, Maria R.;Minchiotti, Gabriella
代谢产物正在成为代谢通量、细胞信号传导和细胞命运的表观遗传调节之间串扰的关键介质。我们发现，非必需氨基酸L-脯氨酸（L-Pro）作为一种信号分子，促进胚胎干细胞转化为间充质样，纺锤形，高运动性，侵入性多能干细胞。这种胚胎干细胞向间充质样转化（esMT）伴随着H3K9和H3K36甲基化状态的全基因组重塑。同样，L-Pro诱导的esMT在L-Pro停药后或通过添加抗坏血酸（维生素C）完全可逆，这反过来又降低了H3K9和H3K36甲基化，促进了间充质样向胚胎干细胞的转变（MesT）。这些发现表明，L-Pro，这是由细胞外基质的蛋白水解重塑，可能作为一个微环境的线索，以控制干细胞的行为。L-Pro诱导可逆的胚胎干细胞向间充质样转化（esMT）esMT的特征在于E-钙粘蛋白的动态再分布，L-Pro充当重塑H3K9和H3K36甲基化的表观遗传修饰剂，L-Pro和维生素C调节esMT-MesT可塑性，调节H3K9/H3K36甲基化。报道L-脯氨酸作为胚胎干细胞（ESC）中的表观遗传修饰剂，诱导可逆的胚胎干细胞向间充质样转化，其将致密的ESC转化为高度运动的侵入性干细胞。维生素C抵消L-脯氨酸促进间充质样胚胎干细胞的转变。这些发现加强了氨基酸作为干细胞行为关键调节因子的作用。
Metabolites are emerging as key mediators of crosstalk between metabolic flux, cellular signaling, and epigenetic regulation of cell fate. We found that the nonessential amino acid L-proline (L-Pro) acts as a signaling molecule that promotes the conversion of embryonic stem cells into mesenchymal-like, spindle-shaped, highly motile, invasive pluripotent stem cells. This embryonic-stem-cell-to-mesenchymal-like transition (esMT) is accompanied by a genome-wide remodeling of the H3K9 and H3K36 methylation status. Consistently, L-Pro-induced esMT is fully reversible either after L-Pro withdrawal or by addition of ascorbic acid (vitamin C), which in turn reduces H3K9 and H3K36 methylation, promoting a mesenchymal-like-to-embryonic-stem-cell transition (MesT). These findings suggest that L-Pro, which is produced by proteolytic remodeling of the extracellular matrix, may act as a microenvironmental cue to control stem cell behavior. L-Pro induces a reversible embryonic-stem-to-mesenchymal-like transition (esMT) The esMT is characterized by a dynamic redistribution of E-cadherin L-Pro acts as an epigenetic modifier remodeling H3K9 and H3K36 methylation L-Pro and vitamin C regulate esMT-MesT plasticity modulating H3K9/H3K36 methylation Comes et al. report that L-proline acts as an epigenetic modifier in embryonic stem cells (ESCs) inducing a reversible embryonic-stem-to-mesenchymal-like transition, which converts compacted ESCs into highly motile, invasive stem cells. Vitamin C counteracts L-proline promoting a mesenchymal-like-to-embryonic-stem-cell transition. These findings strengthen the role of the amino acids as key regulators of stem cell behavior.
登录
查看更多内容
DOI：
10.1126/science.1226603
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shyh-Chang N;Locasale JW;Lyssiotis CA;Zheng Y;Teo RY;Ratanasirintrawoot S;Zhang J;Onder T;Unternaehrer JJ;Zhu H;Asara JM;Daley GQ;Cantley LC
通讯作者：
Cantley LC
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
21.3
作者：
Jiang, Jianming;Chan, Yun-Shen;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
影响因子：
4
作者：
Fico, Annalisa;Manganelli, Genesia;Filosa, Stefania
通讯作者：
Filosa, Stefania
影响因子：
64.5
作者：
Katada, Sayako;Imhof, Axel;Sassone-Corsi, Paolo
通讯作者：
Sassone-Corsi, Paolo