Short telomeres impede germ cell specification by upregulating MAPK and TGFβsignaling  

作　　者：Chenglei Tian Dai Heng Nannan Zhao Linlin Liu Xiaoyan Sheng Jiyu Chen &Lin Liu 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,Nankai University,Tianjin 300350,China [2]Haihe Laboratory of Cell Ecosystem,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300020,China [3]Frontiers Science Center for Cell Responses,College of Life Sciences,Nankai University,Tianjin 300071,China [4]Institute of Translational Medicine,Tianjin Union Medical Center,Nankai University,Tianjin 300000,China [5]The Danish Stem Cell Center,University of Copenhagen,Blegdamsvej 3B,DK-2200 Copenhagen N,Denmark

出　　处：《Science China(Life Sciences)》2023年第2期324-339,共16页中国科学（生命科学英文版）

基　　金：supported by China National Key R&D Program(2018YFA0107002,2018YFC1003004);the National Natural Science Foundation of China(32030033,31430052)。

摘　　要：Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably,elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Reelongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.

关 键 词：TELOMERE primordial germ cell MAPK TGFΒ chromatin accessibility 

分 类 号：Q75[生物学—分子生物学]