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TET2 haploinsufficiency alters reprogramming into induced pluripotent stem cells.
Stem Cell Research ( IF 1.2 ) Pub Date : 2020-03-06 , DOI: 10.1016/j.scr.2020.101755
Lise Secardin 1 , Cintia Elisabeth Gomez Limia 2 , Antonio di Stefano 1 , Martin Hernan Bonamino 3 , Joseph Saliba 1 , Keisuke Kataoka 4 , Stevens K Rehen 5 , Hana Raslova 1 , Caroline Marty 1 , Seishi Ogawa 6 , William Vainchenker 1 , Barbara da Costa Reis Monte-Mor 2 , Isabelle Plo 1
Affiliation  

The discovery of the Ten-Eleven Translocation (TET) protein family was initiated by the identification of the MLL partner TET1, and of mutations in the TET2 gene in hematological malignancies including myeloproliferative neoplasms (MPN). TET1, 2 and 3 proteins hydroxylate 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). Previous studies highlight the involvement of TET proteins in somatic cells reprogramming into induced pluripotent stem cells (iPSC), particularly Tet1 and 2 in mouse and TET1 in human. Here, we asked whether endogenous TET2 knockdown also displays this function. Using different shRNA against TET2, we provide evidence that TET2 strongly decreases the reprogramming of human hematopoietic progenitor cells into iPSC. Importantly, using 2 MPN patients, we observed that TET2 mutations affecting catalytic domain allowed iPSC generation. Instead, using another TET2 and TET3-mutated patient, we could only reprogram IPSC with TET3 mutation alone, suggesting that the type of TET2 mutation and/or the cooperation with TET3 mutations may alter the reprogramming activity. Altogether, this work highlights the importance of endogenous TET in the reprogramming process of human hematopoietic progenitors.



中文翻译:

TET2 单倍体不足会改变重编程为诱导多能干细胞。

10-11 易位 (TET) 蛋白家族的发现始于 MLL 伴侣 TET1 的鉴定,以及包括骨髓增生性肿瘤 (MPN) 在内的血液恶性肿瘤中TET2基因的突变。TET1、2 和 3 蛋白将 5-甲基胞嘧啶 (5-mC) 羟基化为 5-羟甲基胞嘧啶 (5-hmC),并进一步将 5-hmC 氧化为 5-甲酰基胞嘧啶 (5-fC) 和 5-羧基胞嘧啶 (5-caC)。先前的研究强调了 TET 蛋白在体细胞重编程为诱导多能干细胞 (iPSC) 中的作用,特别是小鼠中的 Tet1 和 2 以及人类中的 TET1。在这里,我们询问内源性 TET2 敲除是否也显示此功能。对TET2使用不同的 shRNA,我们提供证据表明 TET2 强烈降低人类造血祖细胞重编程为 iPSC。重要的是,使用 2 名 MPN 患者,我们观察到影响催化结构域的TET2突变允许 iPSC 生成。相反,使用另一个TET2TET3突变的患者,我们只能用TET3突变对 IPSC 进行重编程,这表明TET2突变的类型和/或与TET3突变的合作可能会改变重编程活性。总之,这项工作突出了内源性 TET 在人类造血祖细胞重编程过程中的重要性。

更新日期:2020-03-06
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