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Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs.

Schuster A, Skinner MK, Yan W - Environ Epigenet (2016)

Bottom Line: Gene targets of the altered miRNAs and tRNA 5' halves revealed associations between the altered sncRNAs and differentially DNA methylated regions.Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes.Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Cell Biology, University of Nevada, Reno, NV 89557-0330, USA.

ABSTRACT

Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5' halves of mature tRNAs (5' halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5' halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

No MeSH data available.


Related in: MedlinePlus

GO term analyses of dysregulated sncRNAs in the vinclozolin lineage F3 sperm. (a) Enrichment map of the BP terms associated with redundantly predicted gene targets of down-regulated miRNAs. The genes which were predicted targets of at least two down-regulated miRNAs were analyzed via DAVID for significantly enriched BP terms. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S4. (b) Enrichment map of the BP terms associated with redundantly predicted gene targets of 5′ halves. The genes which were predicted targets of at least three dysregulated 5′ halves were analyzed via DAVID for significantly enriched BP terms. A Benjamini value ≤0.05 was used to define significance. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S5
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Figure 3: GO term analyses of dysregulated sncRNAs in the vinclozolin lineage F3 sperm. (a) Enrichment map of the BP terms associated with redundantly predicted gene targets of down-regulated miRNAs. The genes which were predicted targets of at least two down-regulated miRNAs were analyzed via DAVID for significantly enriched BP terms. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S4. (b) Enrichment map of the BP terms associated with redundantly predicted gene targets of 5′ halves. The genes which were predicted targets of at least three dysregulated 5′ halves were analyzed via DAVID for significantly enriched BP terms. A Benjamini value ≤0.05 was used to define significance. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S5

Mentions: To investigate the putative targets of the transgenerationally altered sperm miRNAs and 5′ halves, a gene ontology (GO) term enrichment analysis was performed on the genes that were targeted by more than one sncRNA. The miRNA target genes that had at least two miRNAs were split into redundant up- and down-regulated miRNA target lists. Searching the Database for Annotation, Visualization and Integrated Discovery (DAVID) for enriched biological process (BP), molecular function (MF), cellular component (CC), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed several significant (Benjamini ≤ 0.05) results for the redundant down-regulated miRNA targets, but none for the up-regulated miRNA (Table S4). An enrichment map of the significant BP genes (Fig. 3a) shows that the redundantly targeted genes are relevant to apoptosis, early development, kinase activity, regulation of transcription, and the nervous system (i.e. its development and synaptic signaling). Significant CC genes also revealed that many of the genes localize in various nervous system cells (e.g. “synapse part”) and the only significant KEGG pathway identified was “axon guidance” (Table S4).


Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs.

Schuster A, Skinner MK, Yan W - Environ Epigenet (2016)

GO term analyses of dysregulated sncRNAs in the vinclozolin lineage F3 sperm. (a) Enrichment map of the BP terms associated with redundantly predicted gene targets of down-regulated miRNAs. The genes which were predicted targets of at least two down-regulated miRNAs were analyzed via DAVID for significantly enriched BP terms. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S4. (b) Enrichment map of the BP terms associated with redundantly predicted gene targets of 5′ halves. The genes which were predicted targets of at least three dysregulated 5′ halves were analyzed via DAVID for significantly enriched BP terms. A Benjamini value ≤0.05 was used to define significance. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S5
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4933025&req=5

Figure 3: GO term analyses of dysregulated sncRNAs in the vinclozolin lineage F3 sperm. (a) Enrichment map of the BP terms associated with redundantly predicted gene targets of down-regulated miRNAs. The genes which were predicted targets of at least two down-regulated miRNAs were analyzed via DAVID for significantly enriched BP terms. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S4. (b) Enrichment map of the BP terms associated with redundantly predicted gene targets of 5′ halves. The genes which were predicted targets of at least three dysregulated 5′ halves were analyzed via DAVID for significantly enriched BP terms. A Benjamini value ≤0.05 was used to define significance. The results of the DAVID analysis were used to generate an enrichment map, grouping related BP terms into clusters. The text overlaying each cluster describes the unifying “theme” of that cluster (chosen by the authors). The individual BP terms are described in more detail in Table S5
Mentions: To investigate the putative targets of the transgenerationally altered sperm miRNAs and 5′ halves, a gene ontology (GO) term enrichment analysis was performed on the genes that were targeted by more than one sncRNA. The miRNA target genes that had at least two miRNAs were split into redundant up- and down-regulated miRNA target lists. Searching the Database for Annotation, Visualization and Integrated Discovery (DAVID) for enriched biological process (BP), molecular function (MF), cellular component (CC), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed several significant (Benjamini ≤ 0.05) results for the redundant down-regulated miRNA targets, but none for the up-regulated miRNA (Table S4). An enrichment map of the significant BP genes (Fig. 3a) shows that the redundantly targeted genes are relevant to apoptosis, early development, kinase activity, regulation of transcription, and the nervous system (i.e. its development and synaptic signaling). Significant CC genes also revealed that many of the genes localize in various nervous system cells (e.g. “synapse part”) and the only significant KEGG pathway identified was “axon guidance” (Table S4).

Bottom Line: Gene targets of the altered miRNAs and tRNA 5' halves revealed associations between the altered sncRNAs and differentially DNA methylated regions.Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes.Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Physiology and Cell Biology, University of Nevada, Reno, NV 89557-0330, USA.

ABSTRACT

Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5' halves of mature tRNAs (5' halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5' halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

No MeSH data available.


Related in: MedlinePlus