Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis.
Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis.
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DOI：
10.1126/sciadv.abm3470
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发表时间：
2022-03-04
期刊：
影响因子：
13.6
通讯作者：
Dawlaty MM
中科院分区：
文献类型：
--
作者：
Ma L;Tang Q;Gao X;Lee J;Lei R;Suzuki M;Zheng D;Ito K;Frenette PS;Dawlaty MM
10-11易位(Tet)酶通过氧化5-甲基胞嘧啶促进DNA去甲基化。它们在发育过程中表达，是小鼠原肠发育所必需的。然而，它们的原肠后发育功能还没有很好地确定。我们发现，所有三种Tet酶的全局或内皮特异性丢失在原肠形成后立即导致造血干细胞和祖细胞(HSPC)数量减少，并导致妊娠中期小鼠胚胎的死亡。这是由于内皮细胞(ECs)来源的HSPC的规格存在缺陷，这损害了原始和最终的造血。从机制上讲，内皮细胞中Tet酶的丢失导致了核因子κB1和主要的造血转录因子(GATA1/2、RUNX1和GFI1b)的高甲基化和下调。在缺乏Tet的内皮细胞中恢复Tet催化活性或过度表达这些因子可以挽救造血缺陷。这建立了Tet酶作为ECs中造血程序的激活剂，用于在胚胎发育期间指定HSPC，这与它们在成人造血中的作用不同，这意味着从多能细胞中分化出HSPC。Tet酶通过激活造血基因，促进胚胎发育过程中造血祖细胞的产生。
Ten-eleven translocation (Tet) enzymes promote DNA demethylation by oxidizing 5-methylcytosine. They are expressed during development and are essential for mouse gastrulation. However, their postgastrulation functions are not well established. We find that global or endothelial-specific loss of all three Tet enzymes immediately after gastrulation leads to reduced number of hematopoietic stem and progenitor cells (HSPCs) and lethality in mid-gestation mouse embryos. This is due to defects in specification of HSPCs from endothelial cells (ECs) that compromise primitive and definitive hematopoiesis. Mechanistically, loss of Tet enzymes in ECs led to hypermethylation and down-regulation of NFκB1 and master hematopoietic transcription factors (Gata1/2, Runx1, and Gfi1b). Restoring Tet catalytic activity or overexpression of these factors in Tet-deficient ECs rescued hematopoiesis defects. This establishes Tet enzymes as activators of hematopoiesis programs in ECs for specification of HSPCs during embryogenesis, which is distinct from their roles in adult hematopoiesis, with implications in deriving HSPCs from pluripotent cells. Tet enzymes promote emergence of hematopoietic progenitor cells during embryogenesis by activating hematopoietic genes.
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影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
64.8
作者：
Chen, Michael J.;Yokomizo, Tomomasa;Zeigler, Brandon M.;Dzierzak, Elaine;Speck, Nancy A.
通讯作者：
Speck, Nancy A.
影响因子：
8.8
作者：
Ito, Kyoko;Lee, Joun;Ito, Keisuke
通讯作者：
Ito, Keisuke
影响因子：
11.8
作者：
Dawlaty, Meelad M.;Breiling, Achim;Le, Thuc;Raddatz, Guenter;Barrasa, M. Inmaculada;Cheng, Albert W.;Gao, Qing;Powell, Benjamin E.;Li, Zhe;Xu, Mingjiang;Faull, Kym F.;Lyko, Frank;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I