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 reversion. 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 reaction. In contrast, JmjC-domain-containing proteins remove methyl groups from histones through a hydroxylation reaction that requires alpha-ketoglutarate and Fe(II) as cofactors. Although an increasing number of histone demethylases have been identified and biochemically characterized, 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.

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…HATs activate gene expression, while HDACs inhibit gene expression. Recent research has identified a critical role for the JHMD2A (Jumonji C-terminal containing histone demethylase 2A) histone demethylase in male infertility and spermatogenesis [158,159]. Using knockout mice as models, this study identified a critical role for JHMD2A in the regulation and expression of two genes, protamine 1 (Prm1) and transition nuclear protein 1 (Tnp1) involved in the condensation and proper packaging of chromatin in the male sperm.…”

Transcription and post-transcriptional regulation of spermatogenesis

“…Analysis of the expression of the genes encoding these histone-like and histone variant proteins in Jhdm2a-null mice revealed that JHDM2A specifically regulates the expression of the genes encoding TNP1 and PRM1 (Okada et al 2007). While it is not certain how JHDM2A accomplishes this, Okada et al (2007) obtained evidence strongly suggesting that JHDM2A directly regulates these genes by binding to and removing a negative transcriptional mark: the methyl groups from lysine 9 of histone H3 (H3K9). This suggests that JHDM2A is necessary for the proper chromatin reorganization during spermatid maturation by directly promoting the transcription of the Tnp1 and Prm1 genes.…”

“…As a caveat, it should be noted that the study conducted by Okada et al (2007) was limited to only a few genes, and thus it will be important to broaden the scope of the analysis to identify other JHDM2A target genes. It will then be crucial to elucidate which of these target genes control the dramatic alterations in chromatin that are integral to the final stages of male germ-cell maturation.…”

“…To begin to understand the in vivo significance of histone demethylation, laboratories have begun to examine the phenotypic consequences of knocking out specific histone demethylase genes. A recent study conducted by Okada et al (2007) revealed that knockout of one of these genes causes defects in post-meiotic stages of spermatogenesis. They found that targeted mutation of the catalytic domain of JHDM2A (recently renamed lysine demethylase 3A (KDM3A)) led to drastically reduced sperm count and male infertility (Okada et al 2007).…”

“…A recent study conducted by Okada et al (2007) revealed that knockout of one of these genes causes defects in post-meiotic stages of spermatogenesis. They found that targeted mutation of the catalytic domain of JHDM2A (recently renamed lysine demethylase 3A (KDM3A)) led to drastically reduced sperm count and male infertility (Okada et al 2007). The earliest germ-cell defects occurred in round spermatids, which they found had abnormal morphology and nuclear organization, consistent with the fact that JHDM2A expression normally peaks at this stage.…”