Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis

Nature volume 450, pages 119–123 (2007)Cite this article

Abstract

Recent studies indicate that, similar to other covalent modifications, histone lysine methylation is subject to enzyme-catalysed reversion1,2. So far, LSD1 (also known as AOF2) and the jumonji C (JmjC)-domain-containing proteins have been shown to possess histone demethylase activity. LSD1 catalyses removal of H3K4me2/H3K4me1 through a flavin-adenine-dinucleotide-dependent oxidation reaction3. In contrast, JmjC-domain-containing proteins remove methyl groups from histones through a hydroxylation reaction that requires α-ketoglutarate and Fe(ii) as cofactors4. Although an increasing number of histone demethylases have been identified and biochemically characterized1,2, their biological functions, particularly in the context of an animal model, are poorly characterized. Here we use a loss-of-function approach to demonstrate that the mouse H3K9me2/1-specific demethylase JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) is essential for spermatogenesis. We show that Jhdm2a-deficient mice exhibit post-meiotic chromatin condensation defects, and that JHDM2A directly binds to and controls the expression of transition nuclear protein 1 (Tnp1) and protamine 1 (Prm1) genes, the products of which are required for packaging and condensation of sperm chromatin. Thus, our work uncovers a role for JHDM2A in spermatogenesis and reveals transition nuclear protein and protamine genes as direct targets of JHDM2A.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Jhdm2a expression is largely restricted to post-meiotic male germ cells.
Figure 2: Jhdm2a mutant mice are hypomorphic.
Figure 3: Defective chromatin condensation in Jhdm2a G / G spermatids.
Figure 4: JHDM2A positively regulates Tnp1 and Prm1 genes in round spermatids.

Similar content being viewed by others

References

  1. Klose, R. J. & Zhang, Y. Regulation of histone methylation by demethylimination and demethylation. Nature Rev. Mol. Cell Biol. 8, 307–318 (2007)

    Article  CAS  Google Scholar 

  2. Shi, Y. & Whetstine, J. R. Dynamic regulation of histone lysine methylation by demethylases. Mol. Cell 25, 1–14 (2007)

    Article  CAS  Google Scholar 

  3. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004)

    Article  CAS  Google Scholar 

  4. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006)

    Article  ADS  CAS  Google Scholar 

  5. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006)

    Article  CAS  Google Scholar 

  6. Hoog, C., Schalling, M., Grunder-Brundell, E. & Daneholt, B. Analysis of a murine male germ cell-specific transcript that encodes a putative zinc finger protein. Mol. Reprod. Dev. 30, 173–181 (1991)

    Article  CAS  Google Scholar 

  7. La Salle, S. & Trasler, J. M. Dynamic expression of DNMT3a and DNMT3b isoforms during male germ cell development in the mouse. Dev. Biol. 296, 71–82 (2006)

    Article  CAS  Google Scholar 

  8. Kosower, N. S., Katayose, H. & Yanagimachi, R. Thiol-disulfide status and acridine orange fluorescence of mammalian sperm nuclei. J. Androl. 13, 342–348 (1992)

    CAS  PubMed  Google Scholar 

  9. Traina, M. E. et al. Long-lasting effects of lindane on mouse spermatogenesis induced by in utero exposure. Reprod. Toxicol. 17, 25–35 (2003)

    Article  CAS  Google Scholar 

  10. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001)

    Article  CAS  Google Scholar 

  11. Payne, C. & Braun, R. E. Histone lysine trimethylation exhibits a distinct perinuclear distribution in Plzf-expressing spermatogonia. Dev. Biol. 293, 461–472 (2006)

    Article  CAS  Google Scholar 

  12. Meistrich, M. L., Trostle-Weige, P. K., Lin, R., Bhatnagar, Y. M. & Allis, C. D. Highly acetylated H4 is associated with histone displacement in rat spermatids. Mol. Reprod. Dev. 31, 170–181 (1992)

    Article  CAS  Google Scholar 

  13. Loukinov, D. I. et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc. Natl Acad. Sci. USA 99, 6806–6811 (2002)

    Article  ADS  CAS  Google Scholar 

  14. Seki, Y. et al. Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev. Biol. 278, 440–458 (2005)

    Article  CAS  Google Scholar 

  15. Sassone-Corsi, P. Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296, 2176–2178 (2002)

    Article  ADS  CAS  Google Scholar 

  16. de Rooij, D. G. & de Boer, P. Specific arrests of spermatogenesis in genetically modified and mutant mice. Cytogenet. Genome Res. 103, 267–276 (2003)

    Article  CAS  Google Scholar 

  17. Cho, C. et al. Haploinsufficiency of protamine-1 or -2 causes infertility in mice. Nature Genet. 28, 82–86 (2001)

    CAS  PubMed  Google Scholar 

  18. Martianov, I. et al. Polar nuclear localization of H1T2, a histone H1 variant, required for spermatid elongation and DNA condensation during spermiogenesis. Proc. Natl Acad. Sci. USA 102, 2808–2813 (2005)

    Article  ADS  CAS  Google Scholar 

  19. Martianov, I. et al. Late arrest of spermiogenesis and germ cell apoptosis in mice lacking the TBP-like TLF/TRF2 gene. Mol. Cell 7, 509–515 (2001)

    Article  ADS  CAS  Google Scholar 

  20. Zhao, M. et al. Transition nuclear proteins are required for normal chromatin condensation and functional sperm development. Genesis 38, 200–213 (2004)

    Article  CAS  Google Scholar 

  21. Matzuk, M. M. & Lamb, D. J. Genetic dissection of mammalian fertility pathways. Nature Cell Biol. 4 (Suppl). s41–s49 (2002)

    Article  Google Scholar 

  22. Pivot-Pajot, C. et al. Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Mol. Cell. Biol. 23, 5354–5365 (2003)

    Article  CAS  Google Scholar 

  23. Okada, Y. et al. Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nature Cell Biol. 8, 1017–1024 (2006)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Ward, V. Madden, R. Bagnell Jr and K. Moore for technical assistance, and K. Yamane for anti-JHDM2B antibody. We are grateful to R. Klose, E. Kallin and K. Gardner for reading of the manuscript. This work was supported by the NIH (Y.Z.), and in part by the Intramural Research Program of the NIH, NIEHS (Y.M.). Y.Z. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions Y.O. and Y.Z. designed the experiments and prepared the manuscript. Y.O. performed the experiments. G.S., M.K.R. and Y.M. generated the chimaera mice from the BayGenomics ES clone.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute,,

    Yuki Okada & Yi Zhang

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA,

    Yuki Okada & Yi Zhang

  3. The Knock Out Core,,

    Greg Scott, Manas K. Ray & Yuji Mishina

  4. Molecular Developmental Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA ,

    Yuji Mishina

Authors
  1. Yuki Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Greg Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manas K. Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuji Mishina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Tables S1-S2 and Supplementary Figures S1-S8 with Legends. (PDF 3073 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okada, Y., Scott, G., Ray, M. et al. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 450, 119–123 (2007). https://doi.org/10.1038/nature06236

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06236

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing