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Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations.

Guerrero-Bosagna C, Weeks S, Skinner MK - PLoS ONE (2014)

Bottom Line: A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp).G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks.Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America; Department of Physics, Biology and Chemistry, Linköping University, Linköping, Sweden.

ABSTRACT
A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations) in the germline (e.g. sperm) that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp). The current observations suggest the transgenerational differential DNA methylation regions (DMR) in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.

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EDM2 incidence in exposure epimutation data sets.(A) Individual occurrence (percentage) of EDM2 in a variety of sets with transgenerational DMR and (B) relative change of EDM2 in these DMR. Columns with ** represent significant change with p<0.01, while columns with * represent significant change with p<0.05.
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pone-0100194-g003: EDM2 incidence in exposure epimutation data sets.(A) Individual occurrence (percentage) of EDM2 in a variety of sets with transgenerational DMR and (B) relative change of EDM2 in these DMR. Columns with ** represent significant change with p<0.01, while columns with * represent significant change with p<0.05.

Mentions: The presence of EDM1 was tested in a variety of transgenerationally altered DMR from sperm and from somatic Sertoli and granulosa cells [44], [45]. These transgenerational F3 generation DMR sets included vinclozolin (52 DMR) [3] dioxin (50 DMR) [2], hydrocarbons, jet fuel (33 DMR) [8], pesticide, permethrin and DEET (367 DMR) [5], plasticizers, BPA and phthalates (198 DMR) [46]. The somatic Sertoli cells and granulosa cells were obtained from F3 generation vinclozolin lineage animals. The DMR were identified with a comparative hybridization MeDIP-Chip analysis on F3 generation control versus exposures lineage cells. A subset of the vinclozolin F3 generation sperm DMR that were confirmed with bisulfite-mass spectrometry were also examined separately and termed “confirmed”. A computer generated random set of DNA sequences using the same genetic features of size and promoter association was created to act as a control for the comparisons (random occurrence). The presence of EDM1 was found to be significantly increased in the vinclozolin DMR set (52 sequences) and in the “confirmed” subset of 16 sequences [3] when compared to a random occurrence set of computer-generated sequences (Figure 2). Interestingly, EDM1 incidence tended to be decreased in sperm DMR from non-vinclozolin exposures or in sets from somatic cells when compared with its occurrence in a random set of sequences. Significant decreases are observed for the sperm plastics and pesticides DMR groups and for the somatic group of Sertoli cells from the vinclozolin exposure lineage (Figure 2A). The presence of EDM2 motif was also tested against the distinct sets of DMR sequences (Figure 3). It was found that EDM2 was significantly increased in the promoter associated sperm DMR sets of dioxin, plastics and pesticides lineages, and in vinclozolin lineage Sertoli cells when compared with its occurrence in a random set of sequences. The most significant increases were in the plastics and pesticides DMR groups with an over two-fold increase in EDM2 incidence. Therefore, two different motifs were identified with EDM1 being primarily associated with vinclozolin lineage DMR and EDM2 being predominant in a number of the other exposures.


Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations.

Guerrero-Bosagna C, Weeks S, Skinner MK - PLoS ONE (2014)

EDM2 incidence in exposure epimutation data sets.(A) Individual occurrence (percentage) of EDM2 in a variety of sets with transgenerational DMR and (B) relative change of EDM2 in these DMR. Columns with ** represent significant change with p<0.01, while columns with * represent significant change with p<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061094&req=5

pone-0100194-g003: EDM2 incidence in exposure epimutation data sets.(A) Individual occurrence (percentage) of EDM2 in a variety of sets with transgenerational DMR and (B) relative change of EDM2 in these DMR. Columns with ** represent significant change with p<0.01, while columns with * represent significant change with p<0.05.
Mentions: The presence of EDM1 was tested in a variety of transgenerationally altered DMR from sperm and from somatic Sertoli and granulosa cells [44], [45]. These transgenerational F3 generation DMR sets included vinclozolin (52 DMR) [3] dioxin (50 DMR) [2], hydrocarbons, jet fuel (33 DMR) [8], pesticide, permethrin and DEET (367 DMR) [5], plasticizers, BPA and phthalates (198 DMR) [46]. The somatic Sertoli cells and granulosa cells were obtained from F3 generation vinclozolin lineage animals. The DMR were identified with a comparative hybridization MeDIP-Chip analysis on F3 generation control versus exposures lineage cells. A subset of the vinclozolin F3 generation sperm DMR that were confirmed with bisulfite-mass spectrometry were also examined separately and termed “confirmed”. A computer generated random set of DNA sequences using the same genetic features of size and promoter association was created to act as a control for the comparisons (random occurrence). The presence of EDM1 was found to be significantly increased in the vinclozolin DMR set (52 sequences) and in the “confirmed” subset of 16 sequences [3] when compared to a random occurrence set of computer-generated sequences (Figure 2). Interestingly, EDM1 incidence tended to be decreased in sperm DMR from non-vinclozolin exposures or in sets from somatic cells when compared with its occurrence in a random set of sequences. Significant decreases are observed for the sperm plastics and pesticides DMR groups and for the somatic group of Sertoli cells from the vinclozolin exposure lineage (Figure 2A). The presence of EDM2 motif was also tested against the distinct sets of DMR sequences (Figure 3). It was found that EDM2 was significantly increased in the promoter associated sperm DMR sets of dioxin, plastics and pesticides lineages, and in vinclozolin lineage Sertoli cells when compared with its occurrence in a random set of sequences. The most significant increases were in the plastics and pesticides DMR groups with an over two-fold increase in EDM2 incidence. Therefore, two different motifs were identified with EDM1 being primarily associated with vinclozolin lineage DMR and EDM2 being predominant in a number of the other exposures.

Bottom Line: A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp).G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks.Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, Washington, United States of America; Department of Physics, Biology and Chemistry, Linköping University, Linköping, Sweden.

ABSTRACT
A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations) in the germline (e.g. sperm) that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp). The current observations suggest the transgenerational differential DNA methylation regions (DMR) in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.

Show MeSH
Related in: MedlinePlus