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Epigenetic landscape of murine testicular histone variants TH2A and TH2B in sperm

ABSTRACT: In this study, chromatin immunoprecipitated sequencing was done for testis specific histone variants of H2B and H2A, TH2B and TH2A to understand the epigenomics of these retained histones, using murine caudal sperm.Our in silico analysis has attributed a myriad of novel functions to sperm retained TH2B with respect to embryo development and spermatogenesis.Also, based on genomic regions, TH2B was observed to be associated with spindle assembly and various meiosis-specific genes, which is an important finding as TH2A/TH2B DKO mice have been reported to have defective cohesin release.We also observed a degree of evolutionary conservation between the TH2B-DNA linkage across human and mouse.This overlap included genes important for embryogenesis. Most importantly, heterogeneity in the epigenetic landscape of TH2A and TH2B was seen which is intriguing as TH2B and TH2A are well reported to be present in the same nucleosomes to promote open chromatin. Additionally, unlike TH2B, TH2A was enriched on the mitochondrial chromosome. We presume that TH2A is associated with mitochondrial DNA inserted in the nuclear DNA and this observation needs further validation.. A comprehensive analysis of these observations indicates novel functions for the sperm retained TH2B and TH2A.

ORGANISM(S): Mus musculus

PROVIDER: GSE181921 | GEO | 2021/12/06

REPOSITORIES: GEO

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Project description:Background Chronic preconception paternal alcohol use modifies the sperm epigenome, inducing fetoplacental growth defects in the offspring of exposed males. A crucial outstanding question in the field of paternal epigenetic inheritance concerns the resilience of the male reproductive tract and the germline's capacity to recover and correct sperm-inherited epigenetic errors after stressor withdrawal. Objectives We set out to determine if measures of the sperm-inherited epigenetic program revert to match the control treatment one month after withdrawing daily alcohol treatments. Materials and Methods Using a voluntary access model, we exposed C57Bl6/J males to 10% alcohol for ten weeks, withdrew alcohol treatment for four weeks, and used RNA sequencing to examine gene expression patterns in the caput section of the epididymis. We then compared the abundance of sperm small RNA species between treatments. Results In the caput section of the epididymis, chronic alcohol exposures induced changes in the transcriptional control of genetic pathways related to mitochondrial function, oxidative phosphorylation, the generalized stress response (EIF2 signaling), and Sirtuin signaling. Subsequent analysis identified region-specific, alcohol-induced changes in mitochondrial DNA copy number across the epididymis, which correlated with increases in the mitochondrial DNA content of alcohol-exposed sperm. Notably, in the corpus section of the epididymis, increases in mitochondrial DNA copy number persisted one month after alcohol cessation. Analysis of sperm noncoding RNAs between Control and Alcohol-Exposed males one month after alcohol withdrawal revealed a ~100-fold increase in mir-196a, a microRNA induced as part of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)-driven cellular antioxidant response. Discussion and Conclusion Our data reveal that alcohol-induced epididymal mitochondrial dysfunction and differences in sperm noncoding RNA content persist after alcohol withdrawal. Further, differences in mir-196a and sperm mitochondrial DNA copy number may serve as viable biomarkers of adverse alterations in the sperm- inherited epigenetic program.

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Epigenetic landscape of murine testicular histone variants TH2A and TH2B in sperm

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