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Isolation and next generation sequencing of epididymal extracellular vesicles reveals segmental patterns of miRNA expression and a potential mechanism for modification of the sperm epigenome.

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE79500 | GEO | 2016/08/25

SECONDARY ACCESSION(S): PRJNA316005

REPOSITORIES: GEO

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Isolation and next generation sequencing of epididymal extracellular vesicles reveals segmental patterns of miRNA expression and a potential mechanism for modification of the sperm epigenome.

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

Small RNAs are trafficked from the epididymis to developing mammalian sperm

Project description:RNAs present in mature mammalian sperm are delivered to the zygote at fertilization, where they have the potential to affect early development. The biogenesis of the small RNA payload of mature sperm is therefore of great interest, as it may be a target of signaling pathways linking paternal conditions to offspring phenotype. Recent studies have suggested the surprising hypothesis that the small RNA payload carried by mature sperm may include RNAs that were not synthesized during testicular spermatogenesis, but that are instead delivered to sperm during the process of post-testicular maturation in the epididymis. To further test this hypothesis, we characterized small RNA dynamics during testicular and post-testicular germ cell maturation in mice, confirming and extending prior observations that testicular germ cell populations carry extremely low levels of tRNA fragments (tRFs), which only become highly abundant only after sperm have entered the epididymis. We examined the sperm RNA repertoire in greater detail, finding that the majority of 5’ tRNA fragments carry a 2’-3’ cyclic phosphate at their 3’ end, pointing to a role for RNaseA or T-family nucleases in tRNA cleavage in the male reproductive tract. The process of small RNA delivery to sperm can be recapitulated in vitro, as caput epididymosomes deliver small RNAs including tRFs and microRNAs to mature testicular spermatozoa. Finally, to definitively identify the tissue of origin for small RNAs in sperm, we carried out tissue-specific metabolic labeling of RNAs in intact mice, finding that mature sperm carry small RNAs that were originally synthesized in the somatic cells of the epididymis. Taken together, our data demonstrates that soma-germline small RNA transfer occurs in male mammals, most likely via vesicular transport from the epididymis to maturing sperm.

2018-07-15 | GSE112990 | GEO

Epididymosomes convey different repertoires of miRNAs throughout the epididymis

Project description:Epididymosomes are small membrane vesicles (50-500nm) secreted by epididymal epithelial cells and involved in post-testicular sperm maturation. While their role in protein transfer to the sperm membrane is well acknowledged, we unveil here their capacity to vehicle microRNAs (miRNAs), which are potent regulators of post-transcriptional gene expression. Using a global microarray approach, we showed that epididymosomes providing from two discrete bovine epididymal regions (caput and cauda) possess distinct miRNA signatures. In addition, we established that miRNA repertoires contained in epididymosomes differ from those of their parent epithelial cells, suggesting that miRNA populations released from the cells may be selectively sorted. Binding of DilC12-labeled epididymosomes to primary cultured epididymal cells was measured by flow cytometry and indicated that epididymosomes from the median caput and their miRNA content may be incorporated into distal caput epithelial cells. Overall, these findings reveal that distinct miRNA repertoires are released into the intraluminal fluid in a region-specific manner and could be involved in a novel mechanism of intercellular communication throughout the epididymis via epididymosomes. We determined the miRNA profiles of epididymosomes isolated by perfusion from caput and cauda regions of the epididymis and compared it with the miRNA content of epididymal epithelial cells from the same regions.

2013-07-01 | E-GEOD-44365 | biostudies-arrayexpress

Epididymosomes convey different repertoires of miRNAs throughout the epididymis

2013-07-01 | GSE44365 | GEO

Sperm heterogeneity and DNMT/TET activities do not account for sperm DNA methylation changes observed in the epididymis

Project description:Following their production in the testis, spermatozoa enter the epididymis to gain their motility and fertilizing abilities. This post-testicular maturation coincides with sperm epigenetic profile changes that influence the progeny outcome. While recent studies underscored the dynamics of small non-coding RNAs in the maturing spermatozoa, little is known regarding sperm methylation changes and their impact at the post-fertilization level. To map out the sperm methylome dynamics, we purified spermatozoa by FACS from the testis and the different epididymal segments (i.e. caput, corpus and cauda) of CAG/su9-DsRed2; Acr3-EGFP transgenic mice. Reduced-Representation Bisulfite Sequencing (RRBS-Seq) performed on DNA from these respective sperm populations indicated that high methylation changes were observed between spermatozoa from the caput vs. testis with 5546 entries meeting our threshold values (q value < 0.01, methylation difference above 25 %). Most of these changes were transitory during epididymal sperm maturation according to the low number of entries identified between spermatozoa from cauda vs. testis.

2022-03-10 | GSE191051 | GEO

The microRNA signature of mouse spermatozoa is dynamically modified during epididymal maturation

Project description:In recent years considerable effort has been devoted to understanding the epigenetic control of sperm development leading to an increased appreciation of the importance of RNA interference pathways, and in particular microRNAs (miRNAs), as key regulators of spermatogenesis and epididymal maturation. It has also been shown that sperm are endowed with an impressive array of miRNA that have been implicated in various aspects of fertilization and embryo development. However, to date there have been no reports on whether the sperm miRNA signature is static or whether it is influenced by their prolonged maturation within the male reproductive tract. To investigate this phenomenon we employed next generation sequencing to systematically profile the miRNA signature of maturing mouse spermatozoa. In so doing we have provided the first evidence for the dynamic post-testicular modification of the sperm miRNA profile under normal physiological conditions. Such modifications include the apparent loss and acquisition of an impressive cohort of some 113 and 115 miRNAs, respectively between the proximal and distal epididymal segments. Interestingly, the majority of these changes occur late in maturation and include the uptake of novel miRNA species in addition to a significant increase in many miRNAs natively expressed in immature sperm. Since sperm are not capable of de novo transcription these findings identify the epididymis as an important site in establishing the sperm epigenome with the potential to condition the peri-conceptual environment of the female reproductive tract, contribute to the inheritance of acquired characteristics, and/or alter the developmental trajectory of the resulting offspring. Examination of the microRNA expression profile in sperm thoughout the mouse epididymis and mouse using next generation sequencing in duplicate.

2015-08-05 | E-GEOD-70198 | biostudies-arrayexpress

Acrylamide modulates the mouse epididymal proteome to drive alterations to the sperm epigenome and dysregulate embryo development

Project description:Paternal exposure to environmental stressors elicits distinct changes to the sperm sncRNA profile; modifications that have significant post-fertilization consequences. Despite this knowledge, there remains limited mechanistic understanding of how paternal exposures modify the sperm sncRNA landscape. Here, we report the acute sensitivity of the sperm sncRNA profile to the reproductive toxicant, acrylamide. Further, we traced the differential accumulation of acrylamide-responsive sncRNAs to coincide with sperm transit of the proximal (caput) segment of the epididymis, wherein acrylamide exposure altered the abundance of several transcription factors implicated in the expression of acrylamide-sensitive sncRNAs. We also identified extracellular vesicles secreted from the caput epithelium in relaying altered sncRNA profiles to maturing spermatozoa, and dysregulated gene expression during early embryonic development following fertilisation by acrylamide-exposed spermatozoa. These data provide mechanistic links to account for how environmental insults can alter the sperm epigenome and compromise the transcriptomic profile of early embryos.

2021-10-04 | GSE162527 | GEO

Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs

Project description:Spermatozoa harbor a complex and environment sensitive pool of small non-coding RNAs (sncRNA)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. We used two distinct paradigms of preconception acute high fat diet to dissect epididymal vs testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs and their fragments (mt-tsRNA) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with BMI and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA-seq of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilisation and implied them in the control of early embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, for the first time in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

2024-04-03 | GSE239815 | GEO

Mitochondrial signals mediate paternal effects on offspring metabolism (Smart-Seq)

Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation [ref], which influences offspring development and adult phenotypic trajectories [refs]. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood [ref]. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.

2024-04-03 | GSE239814 | GEO

Mitochondrial signals mediate paternal effects on offspring metabolism (small RNA-Seq)

Project description:Spermatozoa deliver a complex and environment sensitive pool of small non-coding RNAs (sncRNA) to the oocyte at fertilisation, which influences offspring development and adult phenotypic trajectories. Whether mature spermatozoa in the epididymis can directly sense the environment is still not fully understood. Here, we used two distinct paradigms of preconception acute High Fat Diet challenge to dissect epididymal vs spermatogenic contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNA fragments as sperm-born sensors. In human spermatozoa, we found mt-tsRNAs in linear association with BMI and showed that paternal overweight at conception is sufficient to double offspring obesity risk and compromise metabolic health. Using mouse genetics and metabolic phenotypic data, we show that alterations of mt-tsRNAs are downstream of mitochondrial dysfunction in mice. Most importantly, single embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tsRNAs at fertilisation and implied them in the control of early embryo metabolism. Our study supports the importance of paternal health at conception for offspring metabolism, propose mt-tsRNAs as sperm-born environmental effectors of paternal inheritance and demonstrate, for the first time in a physiological and unperturbed setting, father-to-offspring transfer of sperm mt-tsRNAs at fertilisation.

2024-04-03 | GSE239810 | GEO

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