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"Crews, David"
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Temperature Shift Alters DNA Methylation and Histone Modification Patterns in Gonadal Aromatase (cyp19a1) Gene in Species with Temperature-Dependent Sex Determination
The environment surrounding the embryos has a profound impact on the developmental process and phenotypic outcomes of the organism. In species with temperature-dependent sex determination, gonadal sex is determined by the incubation temperature of the eggs. A mechanistic link between temperature and transcriptional regulation of developmental genes, however, remains elusive. In this study, we examine the changes in DNA methylation and histone modification patterns of the aromatase (cyp19a1) gene in embryonic gonads of red-eared slider turtles (Trachemys scripta) subjected to a temperature shift during development. Shifting embryos from a male-producing temperature (MPT) to a female-producing temperature (FPT) at the beginning of the temperature-sensitive period (TSP) resulted in an increase in aromatase mRNA expression while a shift from FPT to MPT resulted in decreased expression. DNA methylation levels at CpG sites in the promoter of the aromatase gene were high (70-90%) at the beginning of TSP, but decreased in embryos that were incubated at constant FPT and those shifted from MPT to the FPT. This decrease in methylation in the promoter inversely correlated with the expected increase in aromatase expression at the FPT. The active demethylation under the FPT was especially prominent at the CpG site upstream of the gonad-specific TATA box at the beginning of TSP and spread downstream of the gene including exon1 as the gonad development progressed. In embryos incubated at FPT, the promoter region was also labeled by canonical transcriptional activation markers, H3K4me3 and RNA polymerase II. A transcriptional repression marker, H3K27me3, was observed in temperature-shifted gonads of both temperature groups, but was not maintained throughout the development in either group. Our findings suggest that DNA hypomethylation and H3K4me3 modification at the aromatase promoter may be a primary mechanism that releases a transcriptional block of aromatase to initiate a cascade of ovarian differentiation.
Journal Article
Epigenetic Control of Gonadal Aromatase (cyp19a1) in Temperature-Dependent Sex Determination of Red-Eared Slider Turtles
In the red-eared slider turtle (Trachemys scripta), a species with temperature-dependent sex determination (TSD), the expression of the aromatase gene during gonad development is strictly limited to the female-producing temperature. The underlying mechanism remains unknown. In this study, we identified the upstream 5'-flanking region of the aromatase gene, gonad-specific promoter, and the temperature-dependent DNA methylation signatures during gonad development in the red-eared slider turtle. The 5'-flanking region of the slider aromatase exhibited sequence similarities to the aromatase genes of the American alligator, chicken, quail, and zebra finch. A putative TATA box was located 31 bp upstream of the gonad-specific transcription start site. DNA methylation at the CpG sites between the putative binding sites of the fork head domain factor (FOX) and vertebrate steroidogenic factor 1 (SF1) and adjacent TATA box in the promoter region were significantly lower in embryonic gonads at the female-producing temperature compared the male-producing temperature. A shift from male- to female-, but not from female- to male-, producing temperature changed the level of DNA methylation in gonads. Taken together these results indicate that the temperature, particularly female-producing temperature, allows demethylation at the specific CpG sites of the promoter region which leads the temperature-specific expression of aromatase during gonad development.
Journal Article
Epigenetic transgenerational inheritance of altered stress responses
Ancestral environmental exposures have previously been shown to promote epigenetic transgenerational inheritance and influence all aspects of an individual's life history. In addition, proximate life events such as chronic stress have documented effects on the development of physiological, neural, and behavioral phenotypes in adulthood. We used a systems biology approach to investigate in male rats the interaction of the ancestral modifications carried transgenerationally in the germ line and the proximate modifications involving chronic restraint stress during adolescence. We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. This is an important demonstration in an animal that ancestral exposure to an environmental compound modifies how descendants of these progenitor individuals perceive and respond to a stress challenge experienced during their own life history.
Journal Article
Resurrecting the Ancestral Steroid Receptor: Ancient Origin of Estrogen Signaling
Receptors for sex and adrenal steroid hormones are absent from fully sequenced invertebrate genomes and have not been recovered from other invertebrates. Here we report the isolation of an estrogen receptor ortholog from the mollusk Aplysia californica and the reconstruction, synthesis, and experimental characterization of functional domains of the ancestral protein from which all extant steroid receptors (SRs) evolved. Our findings indicate that SRs are extremely ancient and widespread, having diversified from a primordial gene before the origin of bilaterally symmetric animals, and that this ancient receptor had estrogen receptor-like functionality. This gene was lost in the lineage leading to arthropods and nematodes and became independent of hormone regulation in the Aplysia lineage.
Journal Article
Transgenerational Epigenetic Programming of the Brain Transcriptome and Anxiety Behavior
Embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes an epigenetic reprogramming of the male germ-line that is associated with transgenerational adult onset disease states. Further analysis of this transgenerational phenotype on the brain demonstrated reproducible changes in the brain transcriptome three generations (F3) removed from the exposure. The transgenerational alterations in the male and female brain transcriptomes were distinct. In the males, the expression of 92 genes in the hippocampus and 276 genes in the amygdala were transgenerationally altered. In the females, the expression of 1,301 genes in the hippocampus and 172 genes in the amygdala were transgenerationally altered. Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation. An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior. These observations demonstrate that an embryonic exposure to an environmental compound appears to promote a reprogramming of brain development that correlates with transgenerational sex-specific alterations in the brain transcriptomes and behavior. Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.
Journal Article
Transgenerational epigenetic imprints on mate preference
Environmental contamination by endocrine-disrupting chemicals (EDC) can have epigenetic effects (by DNA methylation) on the germ line and promote disease across subsequent generations. In natural populations, both sexes may encounter affected as well as unaffected individuals during the breeding season, and any diminution in attractiveness could compromise reproductive success. Here we examine mate preference in male and female rats whose progenitors had been treated with the antiandrogenic fungicide vinclozolin. This effect is sex-specific, and we demonstrate that females three generations removed from the exposure discriminate and prefer males who do not have a history of exposure, whereas similarly epigenetically imprinted males do not exhibit such a preference. The observations suggest that the consequences of EDCs are not just transgenerational but can be \"transpopulational\", because in many mammalian species, males are the dispersing sex. This result indicates that epigenetic transgenerational inheritance of EDC action represents an unappreciated force in sexual selection. Our observations provide direct experimental evidence for a role of epigenetics as a determinant factor in evolution.
Journal Article
Identification of a Third Distinct Estrogen Receptor and Reclassification of Estrogen Receptors in Teleosts
This paper describes three distinct estrogen receptor (ER) subtypes: ERα , ERβ , and a unique type, ERγ , cloned from a teleost fish, the Atlantic croaker Micropogonias undulatus; the first identification of a third type of classical ER in vertebrate species. Phylogenetic analysis shows that ERγ arose through gene duplication from ERβ early in the teleost lineage and indicates that ERγ is present in other teleosts, although it has not been recognized as such. The Atlantic croaker ERγ shows amino acid differences in regions important for ligand binding and receptor activation that are conserved in all other ERγ s. The three ER subtypes are genetically distinct and have different distribution patterns in Atlantic croaker tissues. In addition, ERβ and ERγ fusion proteins can each bind estradiol-17β with high affinity. The presence of three functional ERs in one species expands the role of ER multiplicity in estrogen signaling systems and provides a unique opportunity to investigate the dynamics and mechanisms of ER evolution.
Journal Article
Two Hits of EDCs Three Generations Apart: Effects on Social Behaviors in Rats, and Analysis by Machine Learning
All individuals are directly exposed to extant environmental endocrine-disrupting chemicals (EDCs), and indirectly exposed through transgenerational inheritance from our ancestors. Although direct and ancestral exposures can each lead to deficits in behaviors, their interactions are not known. Here we focused on social behaviors based on evidence of their vulnerability to direct or ancestral exposures, together with their importance in reproduction and survival of a species. Using a novel “two hits, three generations apart” experimental rat model, we investigated interactions of two classes of EDCs across six generations. PCBs (a weakly estrogenic mixture Aroclor 1221, 1 mg/kg), Vinclozolin (antiandrogenic, 1 mg/kg) or vehicle (6% DMSO in sesame oil) were administered to pregnant rat dams (F0) to directly expose the F1 generation, with subsequent breeding through paternal or maternal lines. A second EDC hit was given to F3 dams, thereby exposing the F4 generation, with breeding through the F6 generation. Approximately 1200 male and female rats from F1, F3, F4 and F6 generations were run through tests of sociability and social novelty as indices of social preference. We leveraged machine learning using DeepLabCut to analyze nuanced social behaviors such as nose touching with accuracy similar to a human scorer. Surprisingly, social behaviors were affected in ancestrally exposed but not directly exposed individuals, particularly females from a paternally exposed breeding lineage. Effects varied by EDC: Vinclozolin affected aspects of behavior in the F3 generation while PCBs affected both the F3 and F6 generations. Taken together, our data suggest that specific aspects of behavior are particularly vulnerable to heritable ancestral exposure of EDC contamination, that there are sex differences, and that lineage is a key factor in transgenerational outcomes.
Journal Article
The (bi)sexual brain
When it comes to sexual behaviour in vertebrates, the two sexes are more alike than different. Yet whilst their bodies are usually male or female, their brains are bisexual and intrinsically capable of behaving as either sex.
Journal Article