m(6)A reader protein YTHDF2 regulates spermatogenesis by timely clearance of phase-specific transcripts

Qi, Meijie1,2; Sun, Haifeng1; Guo, Yueshuai1; Zhou, Yu1; Gu, Xueying1; Jin, Jiachuan1; Chen, Xiaoxu1; Wang, Fangzhu3; Ma, Honghui4; Guo, Xuejiang1; Chen, Hao5; Shen, Bin1,6,7,8

2021-11-01

10.1111/cpr.13164

CELL PROLIFERATION   影响因子和分区

0960-7722

1365-2184

Objectives Accumulating evidences show that the regulatory network of m(6)A modification is essential for mammalian spermatogenesis. However, as an m(6)A reader, the roles of YTHDF2 remain enigmatic due to the lack of a proper model. Here, we employed the germ cell conditional knockout mouse model and explored the function of YTHDF2 in spermatogenesis. Materials and methods Ythdf2 germ cell conditional knockout mice were obtained by crossing Ythdf2-floxed mice with Vasa-Cre and Stra8-Cre mice. Haematoxylin and eosin (HE) staining, immunofluorescent staining and Western blotting were used for phenotyping. CASA, IVF and ICSI were applied for sperm function analysis. RNA-seq, YTHDF2-RIP-seq and quantitative real-time PCR were used to explore transcriptome changes and molecular mechanism analysis. Results Our results showed that YTHDF2 was highly expressed in spermatogenic cells. The germ cell conditional knockout males were sterile, and their sperm displayed malformation, impaired motility, and lost fertilization ability. During differentiated spermatogonia transiting to pachytene spermatocyte, most m(6)A-modified YTHDF2 targets that were degraded in control germ cells persisted in pachytene spermatocytes of Ythdf2-vKO mice. These delayed mRNAs were mainly enriched in pathways related to the regulation of transcription, and disturbed the transcriptome of round spermatid and elongated spermatid subsequently. Conclusion Our data demonstrate that YTHDF2 facilitates the timely turnover of phase-specific transcripts to ensure the proper progression of spermatogenesis, which highlights a critical role of YTHDF2 in spermatogenesis.

m(6)A male sterility mRNA clearance spermatogenesis Ythdf2

SCI

英语

通讯

National Key Research and Development Program of China[2016YFC1000600] ; National Natural Science Foundation of China[31970796]

Cell Biology

Cell Biology

WOS:000723905700001

WILEY

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Nanjing Med Univ, State Key Lab Reprod Med, Nanjing 211166, Peoples R China
2.Univ Sci & Technol China, Affiliated Hosp USTC 1, Ctr Reprod Med, Div Life Sci & Med, Hefei, Peoples R China
3.Gansu Prov Matern & Child Care Hosp, Reprod Med Ctr, Lanzhou, Peoples R China
4.Tongji Univ, Shanghai East Hosp, Dept Cardiol, Sch Med, Shanghai, Peoples R China
5.Southern Univ Sci & Technol, Sch Med, Dept Human Cell Biol & Genet, Shenzhen 518055, Peoples R China
6.Nanjing Med Univ, Gusu Sch, Nanjing, Peoples R China
7.Nanjing Med Univ, Sch Publ Hlth, Ctr Global Hlth, Nanjing, Peoples R China
8.Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Womens Hosp, Nanjing, Peoples R China

Qi, Meijie,Sun, Haifeng,Guo, Yueshuai,et al. m(6)A reader protein YTHDF2 regulates spermatogenesis by timely clearance of phase-specific transcripts[J]. CELL PROLIFERATION,2021.

Qi, Meijie.,Sun, Haifeng.,Guo, Yueshuai.,Zhou, Yu.,Gu, Xueying.,...&Shen, Bin.(2021).m(6)A reader protein YTHDF2 regulates spermatogenesis by timely clearance of phase-specific transcripts.CELL PROLIFERATION.

Qi, Meijie,et al."m(6)A reader protein YTHDF2 regulates spermatogenesis by timely clearance of phase-specific transcripts".CELL PROLIFERATION (2021).