The histone methyltransferase SETD2 is required for expression of acrosin-binding protein 1 and protamines and essential for spermiogenesis in mice

• Published in: The Journal of biological chemistry Vol. 293; no. 24; pp. 9188 - 9197
• Main Authors: Zuo, Xiaoli, Rong, Bowen, Li, Li, Lv, Ruitu, Lan, Fei, Tong, Ming-Han
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.06.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Acrosome - metabolism; Acrosome - pathology; acrosome biogenesis; Animals; Carrier Proteins - genetics; Cells, Cultured; Developmental Biology; Gene Deletion; Gene Expression Regulation, Developmental; Histone Code; histone methylation; histone modification; Histone-Lysine N-Methyltransferase - genetics; histone-to-protamine transition; Infertility, Male - genetics; Infertility, Male - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Protamines - genetics; reproduction; Setd2; Spermatids - cytology; Spermatids - metabolism; Spermatids - pathology; Spermatogenesis; spermiogenesis; testis; histone methylation; Setd2; histone modification; acrosome biogenesis; spermatogenesis; histone-to-protamine transition; testis; spermiogenesis; reproduction
• DOI: 10.1074/jbc.RA118.002851
• ISSN: 0021-9258

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.