Abstract
Spermatogenesis is precisely controlled by complex gene expression programs and involves epigenetic reprogramming, including histone modification and DNA methylation. SET domain-containing 2 (SETD2) is the predominant histone methyltransferase catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3) and plays key roles in embryonic stem cell differentiation and somatic cell development. However, its role in male germ cell development remains elusive. Here, we demonstrate an essential role of Setd2 for spermiogenesis, the final stage of spermatogenesis. Using RNA-seq, we found that, in postnatal mouse testes, Setd2 mRNA levels dramatically increase in 14-day-old mice. Using a germ cell-specific Setd2 knockout mouse model, we also found that targeted Setd2 knockout in germ cells causes aberrant spermiogenesis with acrosomal malformation before step 8 of the round-spermatid stage, resulting in complete infertility. Furthermore, we noted that the Setd2 deficiency results in complete loss of H3K36me3 and significantly decreases expression of thousands of genes, including those encoding acrosin-binding protein 1 (Acrbp1) and protamines, required for spermatogenesis. Our findings thus reveal a previously unappreciated role of the SETD2-dependent H3K36me3 modification in spermiogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.
Highlights
Spermatogenesis is precisely controlled by complex gene expression programs and involves epigenetic reprogramming, including histone modification and DNA methylation
We demonstrate that loss of H3K36me[3] by germ cell–specific disruption of Setd[2] leads to impaired spermiogenesis due to significant down-regulation of its direct target genes, which include many critical master regulators for spermiogenesis
Consistent with the mRNA expression, we found that SET domain– containing 2 (SETD2) protein is mainly detected in the nucleus of pachytene spermatocytes and round spermatids, which were confirmed by the counterstaining of peanut agglutinin (PNA), a marker for the acrosome, and ␥H2AX, a marker for the XY body, respectively (Fig. 1A and Fig. S1B) (37)
Summary
Spatial and temporal patterns of Setd[2] and H3K36me[3] distribution during spermatogenesis. To explore the role of Setd[2] and the associated H3K36me[3] during spermatogenesis, we first examined the expression pattern of Sedt[2] in mouse testes. Consistent with the mRNA expression, we found that SETD2 protein is mainly detected in the nucleus of pachytene spermatocytes and round spermatids, which were confirmed by the counterstaining of peanut agglutinin (PNA), a marker for the acrosome, and ␥H2AX, a marker for the XY body, respectively (Fig. 1A and Fig. S1B) (37). SETD2 is present in Sertoli cells as confirmed by counterstaining of GATA4, a marker for Sertoli cells (and round spermatids) (38) (Fig. S1C). As SETD2 is considered the main histone H3K36me[3] methyltransferase in mammals, we analyzed the distribution of
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