Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis  

作　　者：Zhen Lin Phillip J Hsu Xudong Xing Jianhuo Fang Zhike Lu Qin Zou Ke-Jia Zhang Xiao Zhang Yuchuan Zhou Teng Zhang Youcheng Zhang Wanlu Song Guifang Jia Xuerui Yang Chuan He Ming-Han Tong 

机构地区：[1]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 [2]Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chica- go, IL 60637, USA [3]MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China [4]Synthetic and Functional Biomolecules Center, Beo'ing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Min- istry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China

出　　处：《Cell Research》2017年第10期1216-1230,共15页细胞研究（英文版）

基　　金：M-HT was supported by the Strategic Priority Research Pro- gram of the Chinese Academy of Sciences （XDB19000000）, the Ministry of Science and Technology of China （2014CB943101）, the National Key Research and Development Program of China （2016YFC1000600）, SIBS foundation, the National Natural Science Foundation of China （31471401 and 31671553）, the Science and Technology Commission of Shanghai Municipality （14140901502 and 14JC1407100）. This work was also supported by NIH HG008688 （CH）. CH is an investigator of the Howard Hughes Medical Institute. XY was supported by the National Natural Science Foundation of China （81472855 and 91540109）, the Ministry of Science and Technology of China Grant （2016YFC0906001）. We thank the Histology, Flow Cytometry and Vivarium services at SIBCB, and the Genome Sequencing and High-performance Computing services from the National Protein Science Facility （Beijing） at Tsinghua University.

摘　　要：Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells （SSCs） produce hap- loid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine （m6A）, an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages： undifferentiated spermatogonia, type At spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactiva- tion of the m6A RNA methyltransferase Mettl3 or Mettll4 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Com- bined deletion of Mettl3 and Mettll4 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettll4 in advanced germ cells show normal spermatogenesis. The sper- matids from d6uble-mutant mice exhibit impaired translation of haploid-specific genes that are esseritial for spermio- genesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

关 键 词：m6A RNA modification Mettl3 Mettll4 spermatogonial stem cell SPERMIOGENESIS 

分 类 号：Q78[生物学—分子生物学] S814.1[农业科学—畜牧学]