Biology subjects

MacDonald, J. W.

Publications and source records attributed to MacDonald, J. W..

4 recordsLinked to original sources

bioRxiv2026

EpiBrain: the brain's epigenetic landscape in a snapshot

Epigenetics connect nature with nurture and can help explain how genes, experiences, and the environment influence gene expression to promote individual differences in behavior and mental health. However, how these perturbations induce epigenetic changes across various regions of the brain remains largely unknown. To visualize changes in brains epigenetic landscape at a glance, we develop EpiBrain, a method utilizing whole-brain imaging and registration to capture epigenetic changes in the entire zebrafish brain in a snapshot. Using this method, we uncovered brain-wide epigenetic changes induced by brain activity, chemical exposures, and genetic mutations. We found that gadd45b, an immediate early gene with epigenetic modulatory activity, mediates experience-induced epigenetic changes in the brain, and that these changes contribute to brain activity and behavioral alterations. EpiBrain enables rapid and unbiased assessment of whole-brain epigenetic changes following physiological and disease-relevant perturbations and facilitates mechanistic discoveries at the molecular level.

neuroscience↗

bioRxiv2025

Butyrate rescues chlorpyrifos-induced social deficits through inhibition of class I histone deacetylases

Chlorpyrifos (CPF) is a widely used organophosphate pesticide effective through inhibiting acetylcholinesterase, which leads to the accumulation of acetylcholine and continuous nerve stimulation. In addition to its well-known acute toxicity, exposure to CPF has also been linked to chronic conditions such as an increasing risk of autism spectrum disorder (ASD) and adverse effects on gut health, including disturbances to the gut microbiome and metabolism. However, the underlying mechanism of CPFs contribution to ASD remains unclear, and the roles of the gut microbiome and gut metabolites in CPF-induced neurodevelopmental toxicity remain elusive. Using a high-throughput social behavior assay, we found that embryonic exposure to CPF induced lasting social deficits in zebrafish. Through a small-scale screen of common health beneficial gut microbiome metabolites, we discovered that butyrate effectively rescued CPF-induced social deficits. RNA sequencing of zebrafish brain tissues revealed that early exposure to CPF induced a lasting suppression of neuronal genes, including many ASD risk genes, and elevated expression of circadian genes. Butyrate partially reversed the suppression of key neuronal genes. Butyrate is a non-selective inhibitor of histone deacetylases (HDACs). Through a series of loss-of-function experiments utilizing CRISPR-Cas9-induced knockouts and selective chemical inhibitors, we found that the class I HDAC, HDAC1, most likely mediates butyrates rescue effect. Metabolomics analysis detected changes in several nitrogen metabolism-related pathways in the zebrafish gut following CPF exposure. Metagenomics analysis revealed an increase in abundance of the denitrifying bacteria Pseudomonas and a reduction in the nitric oxide-sensitive bacteria Aeromonas in the CPF-exposed zebrafish gut microbiome. Our results connect CPF-exposure with changes in the gut microbiome, metabolome, epigenetics, gene expression, and behavior, inspiring a novel hypothesis for the underlying molecular mechanisms of CPF-induced neurodevelopmental toxicity. In the long run, our findings may help elucidate how CPF exposure contributes to autism risk and inspire therapeutic developments.

neuroscience↗

bioRxiv2025

From Home to Transcriptome: Comparing the transcriptomic profile of induced immune response via lipopolysaccharide stimulation in homeRNA and venous blood

Remote blood sampling offers multiple advantages over traditional clinic-based blood sampling studies, including greater patient inclusion, more frequent sampling, and broader geographical reach. Combining remote blood sampling with transcriptomic analysis opens potential in translational applications for capturing acute and dynamic immune responses to various exposures. In this study, we establish the feasibility of homeRNA, a capillary blood collection and RNAlater-based stabilization kit, for use in downstream bulk RNA-sequencing applications via capturing a lipopolysaccharide (LPS)-induced inflammatory response. We also compared the baseline gene expression profiles and induced inflammatory response following LPS stimulation between homeRNA-stabilized samples and venous blood stabilized with RNAlater or PAXgene. We found that homeRNA was successfully able to capture an inflammatory response to LPS, specifically targeting various cytokines (e.g., IL6, IL12B, IL1B), chemokines (e.g., CCL3, CXCL10, CCL4), and other transcriptional factors in the toll-like receptor pathway, the primary pathway activated during LPS stimulation. Importantly, we also found that homeRNA captured a LPS-induced inflammatory response comparable to that of venous blood samples stabilized with either RNAlater or PAXgene. Overall, this work demonstrates that the homeRNA platform is compatible with downstream bulk RNA-sequencing analysis and can capture transcriptomic immune responses to a known stimulus which are analogous to results in traditional stabilized venous blood samples.

bioengineering↗

bioRxiv2024

Rigor and Reproducibility of Digital Spatial Profiling on Clinically Sourced Human Tissues

Spatial transcriptomic profiling enables precise quantification of gene expression with simultaneous localization of expression profiles onto tissue structures. This new technology promises to improve our understanding of the disease mechanisms. Therefore, there is intense interest in applying these methods in clinical trials or as laboratory developed tests to aid in diagnosis of disease. Before these technologies can be more broadly deployed in clinical research and diagnostics, it is necessary to thoroughly understand their performance in real world conditions. In this study, we vet technical reproducibility, data normalization methods and assay sensitivity focusing predominantly on one widely used spatial transcriptomic methodology, digital spatial profiling. Using clinically sourced human tissue specimens, we find that digital spatial profiling exhibits high rigor and reproducibility. Our approach lays the foundation for incorporation of digital spatial profiling methods into clinical workflows.

pathology↗