YTHDF2 is essential for spermatogenesis and fertility by mediating a wave of transcriptional transition in spermatogenic cells  

作　　者：Xinxi Zhao Zhen Lin Yong Fan Wenzhi Li Yujie Zhang Fei Li Tong Hong Hua Feng Minghan Tong Ningling Wang Yanping Kuang Qifeng Lyu 

机构地区：[1]Department of Assisted Reproduction,Shanghai Ninth People’s Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China [2]State Key Laboratory of Molecular Biology,Shanghai Key Laboratory of Molecular Andrology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,Chinese Academy of Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China [3]Omics Core,Bio-Med Big Data Center,CAS-MPG Partner Institute for Computational Biology,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai 200031,China

出　　处：《Acta Biochimica et Biophysica Sinica》2021年第12期1702-1712,共11页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grants from the National Key R8cD Program of China(No.2018YFC1003000);the National Natural Science Foundation of China(Nos.81871163 and 81801527).

摘　　要：The dynamic and reversible regulation roles of m^(6)A modification and the characterization of m^(6)A readers have provided new insights into spermatogenesis at the post-transcriptional level.YTHDF2,as an m^(6)A reader,has been reported to mediate the m^(6)A-containing transcript decay during the mouse oocyte maturation,embryonic stem cell differentiation,neural development,and zebrafish maternal-to-zygotic transition.However,the roles of YTHDF2 in mammalian spermatogenesis are uncertain.Here,we generated germ cell-specific Ythdf2 mutants(Ythdf2-vKO)at a C57BL/6J background and demonstrated that YTHDF2 is essential for mouse spermatogenesis and fertility.Ythdf2-vKO provides oligoasthenoteratozoospermia phenotype with increased apoptosis in germ cells.High-throughput RNA-seq analysis showed that a group of mRNAs is upregulated in Ythdf2-vKO mouse testis;further analysis and MeRIP-qPCR data showed that most of the upregulated genes in Ythdf2-vKO mouse testis are modified with m^(6)A and are YTHDF2 candidate binding genes.Interestingly,RNA-seq analysis combined with our previous single-cell transcriptomics data of mouse spermatogenesis pointed out the failure of a wave of transcript transition during the spermatogenesis of Ythdf2-vKO mice,which was confirmed by gene expression analysis using qPCR of diplotene spermatocytes and round spermatids obtained through fluorescence-activated cell sorting.Our study demonstrates the fundamental role of YTHDF2 during mouse spermatogenesis and provides a potential candidate for the diagnosis of male infertility with the oligoasthenoteratozoospermia syndrome.

关 键 词：INFERTILITY m6A OLIGOSPERMIA SPERMATOGENESIS YTHDF2 protein 

分 类 号：R69[医药卫生—泌尿科学]