Abstract
Spermatogenesis is a complex process through which male germ line stem cells undergo a multi-step differentiation program and sequentially become spermatogonia, spermatocytes, spermatids, and eventually spermatozoa. In this process, transcription factors act as switches that precisely regulate the expression of genes that in turn control the developmental program of male germ cells. Transcription factors identified to be essential for normal haploid gene expression all display transcription-activating effects and thus serve as the "on" switch for haploid gene expression. Here, we report that ZMYND15 acts as a histone deacetylase-dependent transcriptional repressor and controls normal temporal expression of haploid cell genes during spermiogenesis. Inactivation of Zmynd15 results in early activation of transcription of numerous important haploid genes including Prm1, Tnp1, Spem1, and Catpser3; depletion of late spermatids; and male infertility. ZMYND15 represents the first transcriptional repressor identified to be essential for sperm production and male fertility.
Highlights
Spermatogenesis is a process of cellular multiplication and differentiation through which male germ cells develop from spermatogonial stem cells to spermatozoa with highly specified functions [1, 2]
We report that Zmynd15 encodes a MYND-containing zinc-binding protein that is exclusively expressed in haploid germ cells during spermatogenesis
Deletion of the 5Ј-untranslated region (UTR) of Cxcl16 Resulted in Inactivation of Zmynd15—In our earlier studies designed to investigate the role of scavenger receptors in cardiovascular diseases, we generated Cxcl16 knock-out mice by deleting the 5Ј-UTR and the entire coding region of Cxcl16 using homologous recombination in murine embryonic stem cells [24]
Summary
CREM-tau acts as a main switch for genes required for haploid germ cell development, including Prm, Prm, Tnp, and Tnp2 [21, 22]. TBPL1 (TATA box-binding protein-like 1) is required for spermiogenesis, and inactivation of Tbpl results in a complete arrest of spermiogenesis at step 7 [23]. Many genes that are under the control of TBPl1 fail to be expressed in the Tbpl1-null mice. We report that Zmynd encodes a MYND-containing zinc-binding protein that is exclusively expressed in haploid germ cells during spermatogenesis. ZMYND15 acts as a transcription repressor through the recruitment of histone deacetylase enzymes (HDACs).. Inactivation of Zmynd in mice results in late spermiogenic disruption, causing azoospermia and complete male infertility ZMYND15 acts as a transcription repressor through the recruitment of histone deacetylase enzymes (HDACs). Inactivation of Zmynd in mice results in late spermiogenic disruption, causing azoospermia and complete male infertility
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