HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis

Abstract

The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.

Transcriptome profiling of histone writers/erasers enzymes across spermatogenesis, mature sperm and pre-cleavage embryo: Implications in paternal epigenome transitions and inheritance mechanisms

“…It was shown that class IIa HDACs enzymatic activity depends on their recruitment into a complex containing HDAC3 and RA nuclear receptor (Parra 2015; Fischle et al, 2002), suggesting that these HDACs could mediate chromatin silencing induced by RA signal. HDAC3 was also found increased in the last stages of meiosis, inducing repression of meiotic/spermatogonial genes and activation of postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations (Yin et al, 2021). On the other hand, SIRT6 and SIRT7 were found associated with heterochromatic regions and nucleoli, respectively (Michishita et al, 2005).…”

“…HDAC3 was also found increased in the last stages of meiosis, inducing repression of meiotic/spermatogonial genes and activation of postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations (Yin et al, 2021). On the other hand, SIRT6 and SIRT7 were found associated with heterochromatic regions and nucleoli, respectively (Michishita et al, 2005).…”

The Improvement of Semen Quality by Dietary Fiber Intake Is Positively Related With Gut Microbiota and SCFA in a Boar Model

“…In addition, previous studies have established that supplementing the diets of adult roosters with sodium butyrate can improve semen volume and sperm motility by enhancing antioxidant capacity and testosterone hormone secretion (Alhaj et al, 2018 ). Butyric acid, which acts as a potent inhibitor of histone deacetylase (HDAC), has been reported to be involved in modulating sperm movement (Parab et al, 2015 ) and is a key regulator of the transcriptional program during the meiotic-to-post-meiotic transition in spermatogenesis (Yin et al, 2021 ). Furthermore, butyrate plays an important role in the redox balance (Lin et al, 2014 ), which is very important for spermatogenesis (Sênos and Jones, 2021 ).…”

Isocitrate dehydrogenase 3b is required for spermiogenesis but dispensable for retinal degeneration

“…Additionally, NADH is a required cofactor for key desaturases including delta-6 desaturases in PUFA metabolism 58 . Also, the acetylation of histone tightly regulates sperm development, especially during the late-stage differentiation 59, 60, 61, 62 . During spermiogenesis, matured spermatozoa acquire a highly condensed genome by replacing 95% of histone into protamine, a small protein facilitate chromatin condensation.…”