Previously uncharacterized histone acetyltransferases implicated in mammalian spermatogenesis

Abstract

During spermiogenesis (the maturation of spermatids into spermatozoa) in many vertebrate species, protamines replace histones to become the primary DNA-packaging protein.It has long been thought that this process is facilitated by the hyperacetylation of histone H4. However, the responsible histone acetyltransferase enzymes are yet to be identified. CDY is a human Y-chromosomal gene family expressed exclusively in the testis and implicated in male infertility. Its mouse homolog Cdyl, which is autosomal, is expressed abundantly in the testis. Proteins encoded by CDY and its homologs bear the ''chromodomain,'' a motif implicated in chromatin binding. Here, we show that (i) human CDY and mouse CDYL proteins exhibit histone acetyltransferase activity in vitro, with a strong preference for histone H4; (ii) expression of human CDY and mouse Cdyl genes during spermatogenesis correlates with the occurrence of H4 hyperacetylation; and (iii) CDY and CDYL proteins are localized to the nuclei of maturing spermatids where H4 hyperacetylation takes place. Taken together, these data link human CDY and mouse CDYL to the histone-to-protamine transition in mammalian spermiogenesis. This link offers a plausible mechanism to account for spermatogenic failure in patients bearing deletions of the CDY genes.histone acetylation ͉ spermiogenesis ͉ chromodomain ͉ infertility T he acetylation of N-terminal lysine residues in core histones has been implicated in three distinct cellular processes. The first is the deposition of free histones onto newly synthesized DNA (1). The second is the regulation of gene expression (reviewed in ref.2). The third is the displacement of histones by transition proteins and protamines during vertebrate spermatogenesis (3-6). Various histone acetyltransferase (HAT) enzymes involved in the first two processes have been characterized. HATs involved in the third process have yet to be identified.In mammals and many other vertebrates, dramatic chromatin remodeling occurs during spermiogenesis, whereby histones are displaced from chromatin, first by transition proteins and later by protamines (7). With protamines, DNA in mature spermatozoa is packaged into an extremely condensed, functionally inert configuration (8). Several lines of evidence led to the view that chromatin remodeling during spermiogenesis is facilitated by hyperacetylation of histone H4. First, studies of numerous vertebrate species have shown that H4 hyperacetylation correlates with the occurrence of the histone-to-protamine transition in spermatogenesis. Extensive H4 hyperacetylation occurs in the testes of species where histones are replaced by protamines during spermiogenesis (3-6), but not in species that completely retain somatic-type histones in mature spermatozoa (4, 9). Second, the timing of H4 hyperacetylation is consistent with its role in promoting histone displacement. Studies in the rat, for instance, demonstrated that H4 hyperacetylation during spermiogenesis immediately precedes the histone-to-protamine transition (5, 6). Finally...

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…A family of PRY genes, essential in the regulation of apoptosis is also found in the AZFb region [53]. Whereas small AZFb deletions have been related to variable testicular phenotypes [54], larger AZFb deletions and those that include genes PRY1/PRY2 seem to cause complete meiotic arrest [34]. Recently, studies have revealed that in cases where all the genes in the AZFb region excluding RBMY and PRY are deleted, patients present with hypo spermatogenesis [20].…”

“…Other genes including SMCY, CDY2, XKRY, HSFY, LOC170324, CYorf14, CYorf15A/B, TTY5, TTY6, TTY9, TTY10, TTY13, TTY14, XKRY and RPS4Y2 have been mapped to this region, but their role in the spermatogenic process is not well elucidated yet [1,54]. Recent evidence points to a role of CDY2 in male germ cell development, specifically in the histone to protamine transition [20,55].…”

“…Recent evidence points to a role of CDY2 in male germ cell development, specifically in the histone to protamine transition [20,55]. HSFY encodes for a heat shock factor type DNA binding domain and is predicted to bind to heat shock promoter elements, as a transcriptional activator [54]. Mahanta et al [55] reported that the frequency of Y chromosome micro deletions in XKRY gene is 23.1 %.…”

Susceptibility of gr/gr rearrangements to azoospermia or oligozoospermia is dependent on DAZ and CDY1 gene copy deletions

“…The gr/gr deletions (which is most frequently observed) remove almost half the gene content of AZFc involving two of the four copies of the DAZ (deleted in azoospermia) gene, one of the two copies of CDY1 (chromodomain protein on Y, 1) and BPY2 (basic protein Y-2) genes; the b1/b3 and b2/b3 deletions also remove the similar amount of genetic material and the same genes [14]. Amongst these three, the DAZ and CDY1 are the key genes required for spermatogenesis [15][16][17][18]. The DAZ gene has four functional copies in AZFc locus that encode for a RNA binding protein and is essential to promote germ cell progression to meiosis [15,17].…”

“…The DAZ gene has four functional copies in AZFc locus that encode for a RNA binding protein and is essential to promote germ cell progression to meiosis [15,17]. The CDY1 gene exists in two copies in the AZFc locus and encodes for chromodomain protein 1 which is postulated to be involved in the hyperacetylation of histones in the maturing spermatids [16,18]. Interestingly, loss of DAZ gene copies lead to a reduction in its expression in the testis of infertile men [19].…”