TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells

被引：6

作者：

Yin, Shanshan ^{[1
,2
]}

Zhang, Fangyingnan ^{[1
]}

Song Lin ^{[1
]}

Wei Chen ^{[1
]}

Kai Weng ^{[3
]}

Dan Liu ^{[4
]}

Wang, Chuanle ^{[1
]}

He, Zibin ^{[1
]}

Chen, Yuxi ^{[1
]}

Ma, Wenbin ^{[1
]}

Huang, Junjiu ^{[1
]}

Yan Huang ^{[1
]}

Zhou Songyang ^{[1
,2
,5
]}

机构：

[1] Sun Yat Sen Univ, SYSU BCM Joint Res Ctr, Sch Life Sci, MOE Key Lab Gene Funct & Regulat,Guangzhou Key La, Guangzhou 510275, Peoples R China

[2] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou 510120, Peoples R China

[3] Shanghai Inst Precis Med, Shanghai 200125, Peoples R China

[4] Baylor Coll Med, Verna & Mans Mclean Dept Biochem & Mol Biol, One Baylor Plaza, Houston, TX 77030 USA

[5] Bioland Lab Guangzhou Regenerat Med & Hlth Guangd, Guangzhou 510005, Peoples R China

来源：

STEM CELL REPORTS | 2022年 / 17卷 / 05期

基金：

中国国家自然科学基金;

关键词：

TELOMERE LENGTH; PROTEIN TIN2; DYSKERATOSIS-CONGENITA; 2-CELL EMBRYOS; DNA; COMPLEX; PROTECTION; LOCALIZATION; ELONGATION; SHELTERIN;

D O I：

10.1016/j.stemcr.2022.03.005

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：1183 / 1197

页数：15