Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis (original) (raw)

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.

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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.

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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
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  2. Greg Scott
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  3. Manas K. Ray
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  4. Yuji Mishina
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  5. Yi Zhang
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Correspondence toYi Zhang.

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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

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Editorial Summary

Fertility-linked demethylase

The histone H3K9 demethylase JHDM2A was known to play a role in transcriptional activation mediated by the androgen receptor. Now targeted disruption of the Jhdm2a gene in mice shows that the enzyme is involved in spermatogenesis and regulation of transition nuclear protein and protamine genes. This work points to a role for this histone demethylase in the late stages of sperm production and maturation, and Jhdm2a becomes a possible candidate gene for infertility syndromes that have not yet been fully characterized.