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

Shanshan Yin, Fangyingnan Zhang, Song Lin, Wei Chen, Kai Weng, Dan Liu, Chuanle Wang, Zibin He, Yuxi Chen, Wenbin Ma, Junjiu Huang, Yan Huang, Zhou Songyang

Stem cell reports 2022 May 10

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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. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Shanshan Yin, Fangyingnan Zhang, Song Lin, Wei Chen, Kai Weng, Dan Liu, Chuanle Wang, Zibin He, Yuxi Chen, Wenbin Ma, Junjiu Huang, Yan Huang, Zhou Songyang. TIN2 deficiency leads to ALT-associated phenotypes and differentiation defects in embryonic stem cells. Stem cell reports. 2022 May 10;17(5):1183-1197