Histone demethylase JHDM2A is involved in male infertility and obesity

Abstract

Recent studies indicate that histone lysine methylation is subject to enzyme-catalyzed 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. To elucidate the physiological functions, we generated the knockout mouse model of dimethylated or monomethylated histone 3 lysine 9 (H3K9me2/1)-specific JmjC domain-containing histone demethylase 2A (JHDM2A; also known as JMJD1A and KDM3A) and showed that JHDM2A is essential for spermatogenesis. Jhdm2a-deficient mice exhibited impaired postmeiotic chromatin condensation, which caused infertility, even though 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 it induced the transcriptional activation of these genes by removing H3K9 methylation, which is known as a silencing marker of gene transcription. This work uncovered a role for JHDM2A in spermatogenesis and identified 2 downstream genes that 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.

Figure 1

Dynamic change of genome-wide histone 3 lysine 9 (H3K9) dimethylation (H3K9me2) during male germ cell development. Timing of dimethyl H3K9 methyltransferases (GLP and G9a) and JmjC domain–containing histone demethylase 2A (JHDM2A) expression is also shown. PGC indicates primordial germ cell; SG, spermatogonium; SC, spermatocyte; RS, round spermatid; ES, elongated spermatid.

Figure 2

Immunohistochemical anaylsis of JmjC domain–containing histone demethylase 2A (JHDM2A) in mouse testis. JHDM2A (green) is highly expressed in round spermatids (RS) and not quite merged with gamma histone 2A variant X (γH2AX)-positive (red) spermatogonia (SG) and spermatocytes (SC). JHDM2A-positive signals disappear in elongated spermatids (ES). Cytoplasmic staining of JHDM2A is observed in Sertoli cells (S). Hoechst (DNA) staining is shown as blue.

Figure 3

Impaired spermiogenesis in JmjC domain–containing histone demethylase 2A (Jhdm2a) knockout mice. (A) Abnormal spermatids at step 15 of spermiogenesis. Smaller, round-shaped spermatids are observed in the knockout mice. (B) Ultrastructurally, chromatin condensation is incomplete in the knockout spermatids. Bar = 1 μm.

Figure 4

JmjC domain–containing histone demethylase 2A (Jhdm2a) knockout mouse (KO; left) exhibits obese phenotype.

Figure 5

Summary of molecular events promoted by JmjC domain–containing histone demethylase 2A (JHDM2A).