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

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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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.

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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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Correspondence to Yi Zhang.

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

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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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