Chromatin alterations during the epididymal maturation of mouse sperm refine the paternally inherited epigenome
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PROVIDER: PRJNA769954 | ENA |
REPOSITORIES: ENA
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Project description:Established dogma holds that all facets of chromatin organization and histone posttranslational modification are complete before sperm exits the testes. Using proteomic analysis to contrast immature spermatozoa and mature sperm from the epididymis, we find progressive changes in multiple histone posttranslational modifications, including H3K4me1, H3K27ac H3K79me2, H3K64ac, H3K122ac, H4K16ac, H3K9me2, and H4K20me3. In contrast, levels of H3K4me3 and H3K27me3 remained constant. Using chromatin immunoprecipitation coupled with deep sequencing, we find that changes in H3K27ac and H3K9me2 involve sharpening broad diffuse regions into narrow peaks, centered on promoters and distal enhancers driving embryonic development (H3K27ac) or tissue-specific genes sequestered in lamina-associated domains (H3K9me2). Maturing sperm contain the histone deacetylase enzymes HDAC1 and HDAC3, suggesting the NuRD complex may drive these changes. These data extend our understanding of germline programming and reveal that, in addition to trafficking noncoding RNAs, alterations to histone structure are a core feature of epididymal maturation.
2022-01-01 | GSE185603 | GEO
Project description: Not available
| S-EPMC8734183 | biostudies-literature
Project description:The role that gamete-inherited chromatin states serve in regulating gene expression across generations is poorly understood. To interrogate how histone marks inherited on parental genomes influence gene expression in offspring, we profiled different tissue contexts in worms that inherited the sperm genome lacking the repressive mark H3K27me3. We found that worms that inherited the sperm genome lacking H3K27me3 upregulated genes in all tissues profiled, which included hermaphrodite and male germlines and mixed soma. We found that most upregulated genes were upregulated specifically from sperm alleles and in a tissue-specific manner, highlighting the importance of cellular context in determining which genes are sensitive to upregulation when H3K27me3 repression is absent. To determine whether chromatin states can impact gene expression transgenerationally, i.e. across 3 generations, we profiled gene expression and chromatin states in the germlines of worms that inherited the sperm genome lacking H3K27me3 (F1 generation) and in the germlines of their offspring (F2 generation). We found that genes upregulated in F1 germlines maintained the H3K27me3(-) state of sperm alleles and that the upregulated and H3K27me3(-) state of sperm alleles was maintained in the germlines of their offspring (F2 generation). These findings demonstrate that histone marks can serve as a transgenerational carrier.
2022-05-31 | GSE205113 | GEO
Project description:The proteome of two sperm sources, epididymal and ejaculated sperm, was compared and associated with sperm freezing capacity using samples collected from three wild small ruminants species. Protein identification was performed using two databases separately (Ovis aries and Capra hircus NCBI) and results were later combined.
2021-05-04 | PXD017462 | Pride
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.
2023-06-17 | GSE234834 | GEO
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.
2023-06-13 | GSE234535 | GEO
Project description:Interest in the sperm epigenome continues to grow in view of the realization that it is vulnerable to dynamic modifications arising from a variety of paternal environment exposures and that this legacy can serve as an important determinant of intergenerational inheritance. It has been postulated that such exchange may be communicated to maturing populations of spermatozoa via the transfer of small non-coding RNAs in a mechanism involving epididymosomes; small membrane bound vesicles secreted by the soma of the male reproductive tract (epididymis). Herein we confirm that mouse epididymosomes encapsulate an impressive repertoire of >350 microRNA (miRNA), a majority (~60%) of which are also represented in the miRNA signature of maturing spermatozoa. This includes >50 miRNAs that were found exclusively in epididymal sperm and epididymosomes, but not in the surrounding soma, thus supporting the notion that epididymosomes may selectively deliver regulatory non-coding RNA cargo to maturing sperm. Interestingly, we also documented substantial plasticity in terms of the epididymosome-borne miRNAs, including significant fold changes in the relative abundance of almost half of the miRNAs along the length of the epididymis. Finally, we provide the first direct evidence for the transfer of several prominent miRNAs between mouse epididymosomes and spermatozoa, and in so doing afford novel insight into a mechanism of intercellular communication through which the RNA payload of sperm can be modified during their post-testicular development. Examination of the microRNA expression profile of mouse epididymal epididymosomes using next generation sequencing in triplicate.
2016-08-25 | E-GEOD-79500 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6939365 | biostudies-literature
Project description:Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Prm2-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm`s antioxidant capacity, indicated by downregulation of key proteins like SOD1 and PRDX5, ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.
2020-07-29 | GSE149454 | GEO
Project description:The discovery of RNAs (e.g. mRNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function in delivering additional paternal information aside from solely providing the DNA1. Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress2, 3 and metabolic disorders4-6. How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA-mediated transmission of high-fat diet (HFD)-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m5C, m2G) in sperm 30-40nt RNA fractions that are induced by HFD. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNA-28S), which might be essential in composing a sperm RNA ‘coding signature’ that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m5C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information.
2018-03-06 | GSE97645 | GEO