A Heterozygous Truncating Mutation in BNC1 Causes Male Subfertility: BNC1 Cooperates with TAF7L to Regulate Spermatogenesis

Basonuclin (BNC1) is expressed primarily in proliferative keratinocytes and gametogenic cells. However, its role in spermatogenesis is not clear. Previously we discovered a heterozygous BNC1 truncating mutation in a premature ovarian insufficiency pedigree. In this study, we found that male mice carrying the truncating mutation exhibited sub-fertility. Genome-wide expression profiling and direct binding studies(ChIP-seq) with BNC1 in mouse testis identified several spermatogenesis specific gene promoters targeted by BNC1 including Klhl10, Tex14, and Spatc1. Moreover, biochemical analysis showed that BNC1 was associated with TAF7L, a germ-cell-specific paralogue of the TFIID subunit TAF7, both in vitro and in testis, suggesting that BNC1 might directly cooperate with TAF7L to regulate spermatogenesis. The truncating mutation disabled nucleal translocation of  the BNC1/TAF7L complex, thus disturbing expression of related genes. Similarly, expressions of BNC1, TAF7L, YBX2, ODF1, and GAPDHS were significantly decreased in the testis of men with NOA.The present study adds to the understanding of the physiology of male reproduction and the mechanism of spermatogenic failure in infertile men. Funding: This work was supported by National Key Research and Development Program of China (2017YFC1001003), National Key Research and Development Plan 459 (2017YFC1001303), the National Basic Research Program of China (No.2013CB967404), the National Natural Science Foundation of China (No. 81471421, 81270664), The competent department of Science & Technology Project (No. 2017FZA7013) and the Science Foundation for Distinguished Young Scholars of Zhejiang Province (No.LR14H040001). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The Medical Ethics Committee of Zhejiang University, approved the study protocol.