Home LiteratureArticle Details
PMID: 28809393 Published · ppublish English Journal Article

Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis.

Cell research ·Vol. 27 ·No. 9 ·2017-09-00 ·Pages 1115-1127

Hsu PJ, Zhu Y, Ma H, Guo Y, Shi X, Liu Y, Qi M, Lu Z, Shi H, Wang J, Cheng Y, Luo G, Dai Q, Liu M, Guo X, Sha J, Shen B, He C

Abstract

N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m6A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m6A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m6A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m6A-binding protein that plays critical roles during spermatogenesis.

MeSH Terms
Adenosine/analogs & derivatives,metabolism Animals Base Sequence Female Male Meiotic Prophase I Mice, Inbred C57BL Protein Binding Protein Biosynthesis RNA Helicases/metabolism RNA, Messenger/genetics,metabolism Spermatogenesis Testis/pathology
Chemicals
RNA, Messenger N-methyladenosine RNA Helicases Ythdc2 protein, mouse Adenosine
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Hsu Phillip J
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA. | Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
Zhu Yunfei
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Ma Honghui
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Guo Yueshuai
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Shi Xiaodan
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Liu Yuanyuan
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Qi Meijie
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Lu Zhike
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Shi Hailing
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Wang Jianying
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Cheng Yiwei
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Luo Guanzheng
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Dai Qing
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Liu Mingxi
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Guo Xuejiang
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Sha Jiahao
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Shen Bin
State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
He Chuan
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. | Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA. | Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
References (51)
51 references, click to expand
  1. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.
    Cell. 2015 Jun 4;161(6):1388-99 PMID: 26046440
  2. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells.
    Cell Stem Cell. 2014 Dec 4;15(6):707-19 PMID: 25456834
  3. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA.
    Cell Res. 2017 Mar;27(3):315-328 PMID: 28106072
  4. Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects.
    Nat Methods. 2014 Apr;11(4):399-402 PMID: 24584192
  5. Coordinated histone modifications mediated by a CtBP co-repressor complex.
    Nature. 2003 Apr 17;422(6933):735-8 PMID: 12700765
  6. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data.
    Bioinformatics. 2010 Jan 1;26(1):139-40 PMID: 19910308
  7. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
    Mol Cell. 2013 Jan 10;49(1):18-29 PMID: 23177736
  8. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.
    Nat Chem Biol. 2011 Oct 16;7(12 ):885-7 PMID: 22002720
  9. N6-methyladenosine-dependent regulation of messenger RNA stability.
    Nature. 2014 Jan 2;505(7481):117-20 PMID: 24284625
  10. From birth to death: the complex lives of eukaryotic mRNAs.
    Science. 2005 Sep 2;309(5740):1514-8 PMID: 16141059
  11. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions.
    Genome Biol. 2013 Apr 25;14(4):R36 PMID: 23618408
  12. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine.
    Cell Res. 2014 Dec;24(12):1493-6 PMID: 25412661
  13. Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid.
    Biochemistry. 1977 Apr 19;16(8):1672-6 PMID: 856255
  14. RIBONUCLEIC ACID SYNTHESIS DURING MITOSIS AND MEIOSIS IN THE MOUSE TESTIS.
    J Cell Biol. 1964 Sep;22:521-32 PMID: 14206420
  15. PARalyzer: definition of RNA binding sites from PAR-CLIP short-read sequence data.
    Genome Biol. 2011 Aug 18;12(8):R79 PMID: 21851591
  16. 5'-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA.
    Biochemistry. 1976 Jan 27;15(2):397-401 PMID: 174715
  17. Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish.
    Science. 2012 Apr 13;336(6078):233-7 PMID: 22422859
  18. Meioc maintains an extended meiotic prophase I in mice.
    PLoS Genet. 2017 Apr 5;13(4):e1006704 PMID: 28380054
  19. Inactivation of the Fto gene protects from obesity.
    Nature. 2009 Apr 16;458(7240):894-8 PMID: 19234441
  20. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation.
    Nat Chem Biol. 2014 Feb;10(2):93-5 PMID: 24316715
  21. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions.
    Nature. 2015 Feb 26;518(7540):560-4 PMID: 25719671
  22. Post-transcriptional gene regulation by mRNA modifications.
    Nat Rev Mol Cell Biol. 2017 Jan;18(1):31-42 PMID: 27808276
  23. Nonsense-mediated mRNA decay (NMD) mechanisms.
    Nat Struct Mol Biol. 2009 Feb;16(2):107-13 PMID: 19190664
  24. Organizing principles of mammalian nonsense-mediated mRNA decay.
    Annu Rev Genet. 2013;47:139-65 PMID: 24274751
  25. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.
    Mol Cell. 2010 May 28;38(4):576-89 PMID: 20513432
  26. Dynamic m(6)A mRNA methylation directs translational control of heat shock response.
    Nature. 2015 Oct 22;526(7574):591-4 PMID: 26458103
  27. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.
    Nature. 2012 Apr 29;485(7397):201-6 PMID: 22575960
  28. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.
    Nat Commun. 2016 Aug 25;7:12626 PMID: 27558897
  29. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.
    Mol Cell. 2016 Jul 21;63(2):306-17 PMID: 27373337
  30. Cytoplasmic m6A reader YTHDF3 promotes mRNA translation.
    Cell Res. 2017 Mar;27(3):444-447 PMID: 28106076
  31. Dynamic RNA Modifications in Gene Expression Regulation.
    Cell. 2017 Jun 15;169(7):1187-1200 PMID: 28622506
  32. Cyclosporin A associated helicase-like protein facilitates the association of hepatitis C virus RNA polymerase with its cellular cyclophilin B.
    PLoS One. 2011 Apr 29;6(4):e18285 PMID: 21559518
  33. Structure of the YTH domain of human YTHDF2 in complex with an m(6)A mononucleotide reveals an aromatic cage for m(6)A recognition.
    Cell Res. 2014 Dec;24(12):1490-2 PMID: 25412658
  34. m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition.
    Nature. 2017 Feb 23;542(7642):475-478 PMID: 28192787
  35. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells.
    Proc Natl Acad Sci U S A. 1974 Oct;71(10):3971-5 PMID: 4372599
  36. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain.
    Nat Chem Biol. 2014 Nov;10 (11):927-9 PMID: 25242552
  37. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing.
    Mol Cell. 2016 Feb 18;61(4):507-19 PMID: 26876937
  38. Dynamic RNA modifications in posttranscriptional regulation.
    Mol Cell. 2014 Oct 2;56(1):5-12 PMID: 25280100
  39. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks.
    Nat Protoc. 2012 Mar 01;7(3):562-78 PMID: 22383036
  40. Germline copy number variation in the YTHDC2 gene: does it have a role in finding a novel potential molecular target involved in pancreatic adenocarcinoma susceptibility?
    Expert Opin Ther Targets. 2014 Aug;18(8):841-50 PMID: 24834797
  41. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated.
    Cancer Lett. 2016 Jun 28;376(1):34-42 PMID: 26996300
  42. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.
    Science. 2015 Feb 27;347(6225):1002-6 PMID: 25569111
  43. XRN 5'→3' exoribonucleases: structure, mechanisms and functions.
    Biochim Biophys Acta. 2013 Jun-Jul;1829(6-7):590-603 PMID: 23517755
  44. RNA-methylation-dependent RNA processing controls the speed of the circadian clock.
    Cell. 2013 Nov 7;155(4):793-806 PMID: 24209618
  45. Implementation of meiosis prophase I programme requires a conserved retinoid-independent stabilizer of meiotic transcripts.
    Nat Commun. 2016 Jan 08;7:10324 PMID: 26742488
  46. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.
    Cell Res. 2014 Feb;24(2):177-89 PMID: 24407421
  47. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.
    Cancer Cell. 2017 Jan 9;31(1):127-141 PMID: 28017614
  48. A quantitative analysis of CLIP methods for identifying binding sites of RNA-binding proteins.
    Nat Methods. 2011 May 15;8(7):559-64 PMID: 21572407
  49. PAR-CliP--a method to identify transcriptome-wide the binding sites of RNA binding proteins.
    J Vis Exp. 2010 Jul 02;(41):null PMID: 20644507
  50. MOV10 Is a 5' to 3' RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3' UTRs.
    Mol Cell. 2014 May 22;54(4):573-85 PMID: 24726324
  51. Inactivation or non-reactivation: what accounts better for the silence of sex chromosomes during mammalian male meiosis?
    Chromosoma. 2012 Jun;121(3):307-26 PMID: 22366883
Article Info
Journal
Cell research
Abbr.
Cell Res
ISSN
1748-7838
DOI
10.1038/cr.2017.99
Published
2017-09-00
Epub
2017-00-15
Pages
1115-1127
Language
English
Region
England
NLM ID
9425763
PMCID
PMC5587856
Subset
IM
Grants
NIGMS NIH HHS · R01 GM113194 · United States
NHGRI NIH HHS · RM1 HG008935 · United States
NIGMS NIH HHS · T32 GM007281 · United States
External Links
PubMed source DOI: 10.1038/cr.2017.99 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2