Zmynd15 Encodes a Histone Deacetylase-dependent Transcriptional Repressor Essential for Spermiogenesis and Male Fertility

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.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). Spermatogenesis can be divided into three phases: the mitotic phase (proliferation and differentiation of spermatogonia), the meiotic phase (differentiation of spermatocytes), and spermiogenesis (differentiation of haploid germ cells from round spermatids to elongated spermatids and spermatozoa) (1, 2). Within the seminiferous tubules, the developing male germ cells including spermatogonia, spermatocytes, and spermatids are all in close contact with the cytoplasm of supporting Sertoli cells, and these spermatogenic cells form specific cellular associations, which have been termed stages (3). For example, at stage VII, type A1 spermatogonia, preleptotene spermatocytes, step 7 round spermatids, and step 16 elongated spermatids are associated with each other, whereas type A3 spermatogonia, zygotene spermatocytes, meiotically dividing spermatocytes, and elongating step 12 spermatids are grouped together. Twelve stages (stages I-XII) can be identified in the mouse seminiferous tubules (3). Meiosis is unique to germ cells, and spermiogenesis is unique to male germ cell development. Unique processes often require unique genes and gene products to execute the functions. This may explain why ϳ10% of the entire protein-encoding genes are dedicated to the regulation of spermatogenesis, and spermiogenesis alone involves at least 500 testis-specific genes (4 -6).Another unique feature in the control of gene expression during spermiogenesis is the uncoupling of transcription and translation (7-12), which results from the fact that genes required for late spermiogenesis (step 9 -16 spermatids in mice) have to be transcribed in round spermatids (steps 1-8) because transcription ceases when nuclear elongation and condensation start at step 9 of spermatid development in mice...

Three Testis-Specific Paralogous Serine Proteases Play Different Roles in Murine Spermatogenesis and Are Involved in Germ Cell Survival During Meiosis1

“…6). In particular, Prss42/Tessp-2 protein was detected in secondary spermatocytes and spermatids, which indicated that Prss42/ Tessp-2 mRNA was under translational arrest in primary spermatocytes as is often observed for genes expressed during spermatogenesis [47][48][49][50]. This also suggested that Prss42/ Tessp-2 functioned at the late stages of meiosis and/or during antibodies (B, D).…”

Truncating mutations inTAF4BandZMYND15causing recessive azoospermia

“…Exome sequencing analysis revealed the causative mutations in both families. The genes are considered to be responsible for infertility in the respective families for several reasons: the mutations are very severe and not found in 180 unrelated subjects (the control panel plus the infertile cohort) tested, and mouse knockout models are azoospermic 21 22. We screened the cohort of infertile men for the two genes plus SPAG7 for mutation but did not find any potentially pathogenic variant.…”

Mutation in TDRD9 causes non-obstructive azoospermia in infertile men

“…SPGF14 (MIM 615842) is caused by a heterozygous frameshift mutation in the ZMYND15 gene (MIM 614312). ZMYND15 is suggested to be a histone deacetylase-dependent transcriptional repressor that controls normal temporal expression of haploid genes during spermiogenesis 9. SPGF15 (MIM 616950) is caused by a homozygous splice site mutation in the SYCE1 gene (MIM 611486) 10.…”