TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells.
TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells.
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TIN2 缺陷导致胚胎干细胞出现 ALT 相关表型和分化缺陷
DOI：
10.1016/j.stemcr.2022.03.005
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发表时间：
2022-05-10
影响因子：
5.9
通讯作者：
Zhou Songyang
中科院分区：
文献类型：
--
作者：
Yin, Shanshan;Zhang, Fangyingnan;Song Lin;Wei Chen;Kai Weng;Dan Liu;Wang, Chuanle;He, Zibin;Chen, Yuxi;Ma, Wenbin;Huang, Junjiu;Yan Huang;Zhou Songyang
端粒完整性对胚胎发育至关重要，而核心端粒结合蛋白，如TIN 2，是维持端粒稳定性的关键。在这里，我们报告纯合子Tin 2S 341 X导致小鼠胚胎死亡，并减少衍生的小鼠胚胎干细胞（mESC）中Tin 2的表达。纯合突变型mESC能够自我更新并保持未分化，但显示出许多与端粒（ALT）替代性延长相关的表型，包括过长和异质的端粒，ALT相关的早幼粒细胞白血病（PML）小体增加和染色体末端不稳定。这些细胞还显示Zscan 4表达的上调和DAXX/ATRX和H3 K9 me 3标记在端粒上的靶向升高。此外，突变mESCs的分化能力受到阻碍。分化后，DAXX/ATRX和PML小体与这些细胞中的端粒分离，其中DNA损伤也明显升高。我们的研究结果揭示了mESC与分化细胞对端粒功能障碍的不同反应，并强调了TIN 2在胚胎发育中的关键作用。TIN 2缺陷导致mESCs ALT表型和分化缺陷在TIN 2缺陷mESCs中PML和DAXX/ATRX在端粒上富集在分化时端粒PML和DAXX/ATRX减少TIN 2L和TIN 2S可能在mESCs中具有类似的功能。突变型mESC显示与端粒的交替延长、2C-基因表达的上调和端粒上DAXX/ATRX的富集相关的表型。突变的mESC具有阻碍的分化能力。在分化时，这些细胞显示出升高的DNA损伤和减少的端粒DAXX/ATRX和PML小体。
Telomere integrity is critical for embryonic development, and core telomere-binding proteins, such as TIN2, are key to maintaining telomere stability. Here, we report that homozygous Tin2S341X resulted in embryonic lethality in mice and reduced expression of Tin2 in the derived mouse embryonic stem cells (mESCs). Homozygous mutant mESCs were able to self-renew and remain undifferentiated but displayed many phenotypes associated with alternative lengthening of telomeres (ALT), including excessively long and heterogeneous telomeres, increased ALT-associated promyelocytic leukemia (PML) bodies, and unstable chromosomal ends. These cells also showed upregulation of Zscan4 expression and elevated targeting of DAXX/ATRX and H3K9me3 marks on telomeres. Furthermore, the mutant mESCs were impeded in their differentiation capacity. Upon differentiation, DAXX/ATRX and PML bodies disassociated from telomeres in these cells, where elevated DNA damage was also apparent. Our results reveal differential responses to telomere dysfunction in mESCs versus differentiated cells and highlight the critical role of TIN2 in embryonic development. TIN2 deficiency leads to ALT phenotypes and differentiation defects in mESCs PML and DAXX/ATRX are enriched on telomeres in TIN2-deficient mESCs Telomeric PML and DAXX/ATRX decrease upon differentiation TIN2L and TIN2S may have comparable functions in mESCs In this article, Songyang and colleagues show that Tin2S341X mutation leads to TIN2 deficiency. The mutant mESCs display phenotypes associated with alternative lengthening of telomeres, upregulation of 2C-gene expression, and enrichment of DAXX/ATRX on telomeres. The mutant mESCs have impeded differentiation capacity. Upon differentiation, these cells show elevated DNA damage and decreased telomeric DAXX/ATRX and PML bodies.
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临时细胞性白血病核体的行为是DNA损伤传感器，其对DNA双链断裂的反应由NBS1和激酶ATM，CHK2和ATR调节。
DOI：
10.1083/jcb.200604009
发表时间：
2006-10-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dellaire G;Ching RW;Ahmed K;Jalali F;Tse KC;Bristow RG;Bazett-Jones DP
通讯作者：
Bazett-Jones DP
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
Daxx/Atrx 复合物通过促进 H3K9 三甲基化在 DNA 低甲基化过程中保护串联重复元件
影响因子：
23.9
作者：
He Q;Kim H;Huang R;Lu W;Tang M;Shi F;Yang D;Zhang X;Huang J;Liu D;Songyang Z
通讯作者：
Songyang Z
影响因子：
16
作者：
Chen, Liuh-Yow;Zhang, Yi;Zhang, Qinfen;Li, Hongzhi;Luo, Zhenhua;Fang, Hezhi;Kim, Sok Ho;Qin, Li;Yotnda, Patricia;Xu, Jianming;Tu, Benjamin P.;Bai, Yidong;Zhou Songyang
通讯作者：
Zhou Songyang
影响因子：
11.4
作者：
BRYAN, TM;ENGLEZOU, A;REDDEL, RR
通讯作者：
REDDEL, RR