ATAD2 deficiency leads to subfertility by impairing spermatogenesis in mice

During spermatogenesis, chromatin remodeling regulated by histone modification is essential for spermatogenic cell development, and multiple epigenetic regulators are involved in this process. Recent studies reported that ATAD2 was a newly discovered cancer/testis factor that functioned in chromatin remodeling in somatic cells by binding acetylated histone. However, the physiological role of ATAD2 in spermatogenesis is largely unknown. In this study, we characterized the expression pattern of ATAD2 in mouse testes and found that the highly expressed ATAD2 in the gonads was lowly expressed in meiotic spermatocytes with distinct localization in nucleus, but highly expressed in round spermatids. By generating Atad2 knockout mice using CRISPR/Cas9 technology, we revealed that ATAD2 deletion leads to failure of DSB repair and chromosome synapsis in spermatocytes and impairs spermiogenesis in spermatids. Atad2 knock out (KO) mice were subfertile, as characterized by reduced sperm count, impaired motility, and abnormal morphology. RNA-Seq analysis showed that hundreds of genes were dysregulated in Atad2-KO round spermatids. As revealed by GSEA analysis, the gene set related to spermatid development was downregulated, while gene sets related to chromatin binding and positive and negative DNA-templated transcription were upregulated. In conclusion, our results indicate that ATAD2 contributes to meiotic progression and participates in spermiogenesis by regulating RNA transcription in spermatids.