Journal of Andrology Testis Workshop 2009
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Published-Ahead-of-Print October 29, 2009, DOI:10.2164/jandrol.109.008052

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Histone Demethylase JHDM2A Is Involved in Male Infertility and Obesity

Yuki Okada *, Keisuke Tateishi , and Yi Zhang

* To whom correspondence should be addressed. E-mail: yuki_okada{at}med.unc.edu.

Recent studies indicate that histone lysine methylation is subject to enzyme-catalysed reversion, and jumonji C (JmjC)-domain-containing proteins have been identified as one of the members of histone demethylases. Although an increasing number of histone demethylases have been identified and biochemically characterized, their biological functions are poorly characterized. In order to elucidate the physiological functions, we generated the knockout mouse model of H3K9me2/1-specific demethylase JHDM2A (JmjC-domain-containing histone demethylase 2A, a.k.a. JMJD1A and KDM3A) and showed that JHDM2A is essential for spermatogenesis. Jhdm2a-deficient mice exhibited impaired post-meiotic chromatin condensation, that caused infertility although the hormonal levels were maintained. Further molecular and biochemical analysis revealed that JHDM2A directly bound to the core promoter regions of transition nuclear protein 1 (Tnp1) and protamine 1 (Prm1) genes, and induced the transcriptional activation of these genes by removing H3K9 methylation, that is known as a silencing marker of gene transcription. This work uncovered a role for JHDM2A in spermatogenesis and identified two downstream genes, which are critical for sperm nuclear condensation. In addition, we also showed that JHDM2A plays a role in regulating fat metabolic gene expression in muscle and brown fat tissue, and the knockout mice exhibited obesity and hyperlipidemia. Thus, JHDM2A possesses organ/tissue-specific target genes, and impairment of this molecule cannot be compensated by other JmjC-containing histone demethylases, suggesting the importance of this molecule in vivo.


Key words: Infertility • Sperm • Histone demethylation • Obesity






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