The intrinsic and extrinsic effects of TET proteins during gastrulation.
The intrinsic and extrinsic effects of TET proteins during gastrulation.
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TET蛋白在胃肠道过程中的内在和外在作用。
DOI：
10.1016/j.cell.2022.06.049
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发表时间：
2022-08-18
期刊：
影响因子：
64.5
通讯作者：
Stelzer, Yonatan
中科院分区：
文献类型：
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作者：
Cheng, Saifeng;Mittnenzweig, Markus;Mayshar, Yoav;Lifshitz, Aviezer;Dunjic, Marko;Rais, Yoach;Ben-Yair, Raz;Gehrs, Stephanie;Chomsky, Elad;Mukamel, Zohar;Rubinstein, Hernan;Schlereth, Katharina;Reines, Netta;Orenbuch, Ayelet-Hashahar;Tanay, Amos;Stelzer, Yonatan
所有10-11易位(TET)基因缺失的小鼠表现出早期原肠致死。然而，分离这种胚胎失败的因果关系是具有挑战性的。为了分离Tet丢失的细胞自主效应，我们使用了来自具有部分或全部突变贡献的胚胎的临时单细胞图谱。值得注意的是，当在野生型胚胎中发育时，Tet突变细胞保持了接近完全的分化潜力，而仅由突变细胞组成的胚胎在上胚层到外胚层的转变中存在缺陷，具有退化的中胚层潜力。我们将早期上胚层因子(如Dppa4和GDF3)的表达下调以及未能激活新生中胚层的多种信号(Lefty、Fgf和Notch)映射为Tet丢失表型的可能细胞内在驱动因素。我们进一步认为增强子去甲基化的缺失是潜在的机制。总而言之，我们的工作展示了一种基于时间分化图谱定义内在和外在胚胎基因功能的无偏见方法，并将去甲基化机制的细胞内效应与其更广泛的组织水平的分支分开。具有完全或部分Tet缺陷的嵌合体在原肠发育过程中被定位Tet-TKO细胞扰乱信号，导致倾斜的全胚胎突变原肠形成Tet-TKO细胞在嵌合体环境中保持接近完全的分化潜能失去Tet导致普遍的高甲基化和轻微扰动的基因表达缺乏Tet贡献的单胚胎、单细胞胚胎的时间模型，从其随后的组织水平的分支阐明Tet机制的细胞内在效应。Tet介导的去甲基化以一种谱系和时间特定的方式改变基因表达，但这种改变可以在来自邻近细胞的细胞间信号的存在下克服。
Mice deficient for all ten-eleven translocation (TET) genes exhibit early gastrulation lethality. However, separating cause and effect in such embryonic failure is challenging. To isolate cell-autonomous effects of TET loss, we used temporal single-cell atlases from embryos with partial or complete mutant contributions. Strikingly, when developing within a wild-type embryo, Tet-mutant cells retain near-complete differentiation potential, whereas embryos solely comprising mutant cells are defective in epiblast to ectoderm transition with degenerated mesoderm potential. We map de-repressions of early epiblast factors (e.g., Dppa4 and Gdf3) and failure to activate multiple signaling from nascent mesoderm (Lefty, FGF, and Notch) as likely cell-intrinsic drivers of TET loss phenotypes. We further suggest loss of enhancer demethylation as the underlying mechanism. Collectively, our work demonstrates an unbiased approach for defining intrinsic and extrinsic embryonic gene function based on temporal differentiation atlases and disentangles the intracellular effects of the demethylation machinery from its broader tissue-level ramifications. Chimeras with full or partial Tet deficiency are mapped over the course of gastrulation Tet-TKO cells disrupt signaling, leading to skewed whole-embryo mutant gastrulation Tet-TKO cells retain near-complete differentiation potential in a chimera context Loss of TET leads to pervasive hypermethylation and mildly perturbed gene expression Single-embryo, single-cell temporal models of embryos lacking Tet contribution, either partially or fully, clarify the cell-intrinsic effects of the TET machinery from its subsequent tissue-level ramifications. TET-mediated demethylation alters gene expression in a lineage- and time-specific fashion, but such alterations can be overcome in the presence of inter-cellular signals from neighboring cells.
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DOI：
10.1126/science.1229277
发表时间：
2013-01-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hackett JA;Sengupta R;Zylicz JJ;Murakami K;Lee C;Down TA;Surani MA
通讯作者：
Surani MA
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：
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：
64.8
作者：
Aguilera-Castrejon, Alejandro;Oldak, Bernardo;Hanna, Jacob H.
通讯作者：
Hanna, Jacob H.
影响因子：
4.6
作者：
Chen, CH;Ware, SM;Brown, CW
通讯作者：
Brown, CW