Michael Golding

Hard ticks are a source of public health concern, in part due to their ability to inhabit different environments. In the United States (US), blacklegged ticks (Ixodes scapularis Say), the primary vector of Lyme disease, exhibit various phenotypes depending on their geographic origin (i.e. northern and southern US ticks). Although genetics may partially explain how blacklegged tick populations acclimate to different environmental conditions across the US, epigenetics may also contribute to their success. Epigenetic mechanisms, such as DNA methylation, might modulate gene expression allowing for rapid adaptation. To gain insight into the potential contribution of DNA methylation, an Enzyme-Linked Immunosorbent Assay (ELISA) was utilized to evaluate differences in DNA methylation levels between blacklegged ticks collected from Minnesota (northern region) and Texas (southern region). DNA methylation profiles from both populations were characterized using bisulfite and nanopore sequencing. Our results revealed significant variability in global methylation levels between southern and northern tick populations, as well as highly variable relative expression of genes encoding DNA methyltransferases and demethylases. Overall, northern blacklegged ticks exhibit lower global DNA methylation levels than southern ticks. Basic proline-rich protein, zinc finger protein 501-like protein, and an uncharacterized protein LOC115333191 are among the genes that exhibit lower DNA methylation. Our findings revealed that blacklegged tick populations possess distinctive DNA methylation profiles, which may contribute to their phenotypic plasticity across the US. This study aims to pave the way for future research into the potential molecular mechanisms that allow ticks to successfully acclimatize to environmental changes.

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Small RNAs delivered by sperm can transmit environmentally regulated, epigenetically inherited phenotypes to offspring, yet the mechanisms by which modest changes in sperm microRNA abundance overcome dilution within the much larger egg to influence embryonic development remain unresolved. Here, we show that physiologically relevant variation in individual sperm miRNAs is sufficient to quantitatively program embryonic gene expression and developmental outcomes. Using parthenogenetic and fertilized embryos, we show that as few as 200 molecules of miR-200c-3p or miR-465c-3p induces reproducible, dose-dependent gene expression responses across defined developmental windows. Parthenogenetic embryos faithfully recapitulate early miRNA-driven gene expression changes observed in fertilized embryos, validating their use for isolating early regulatory mechanisms. We further developed AGO2-REMORA, an RNA adenosine base editor fused to Argonaute2 to map miRNA–mRNA interactions in embryos, revealing that early mRNA repression reflects direct miRNA targeting, while transcriptional changes at later stages arise as secondary consequences of these initial interactions. Furthermore, we show that modest elevation of miR-200c-3p during early development is sufficient to induce transcriptional alterations through early development and produce craniofacial phenotypes in late-stage embryos, recapitulating features of fetal alcohol syndrome associated with paternal alcohol consumption. Together, these findings establish a generalizable framework by which small perturbations in sperm miRNA content quantitatively modulate early gene regulatory programs, triggering cascades that persist throughout development and influence offspring phenotype.

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Emerging research reveals that epigenetic mechanisms of paternal inheritance are a significant driver of adverse developmental outcomes, including those associated with fetal alcohol spectrum disorders (FASD). In recognition of the urgent need to understand the combined effects of maternal and paternal alcohol consumption, our laboratory established a preclinical multiplex mouse model to compare alcohol-induced developmental defects in offspring resulting from maternal, paternal, and dual parental exposures. Our findings reveal that both maternal and paternal alcohol consumption independently impair placental development and alter craniofacial patterning in a dose-dependent manner. Strikingly, in the male offspring, we observed an interaction between maternal and paternal alcohol use, with adverse developmental outcomes in the dual-parental offspring exceeding those induced by either maternal or paternal alcohol use alone. Our ongoing experiments reveal that parental alcohol exposure heritably disrupts offspring mitochondrial complex I activity in the placenta and fetal brain. These deficits persist into adulthood, resulting in elevated oxidative stress, chronic inflammation, and premature cellular aging in the brain and liver. Our results underscore that chronic toxicant-induced mitochondrial stress, ­particularly in males, programs enduring bioenergetic dysfunction that elevates the risk of birth defects and long-term disease. These findings emphasize the critical importance of considering both maternal and paternal health in preconception planning.

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