Biology subjects

McClay, J. L.

Publications and source records attributed to McClay, J. L..

5 recordsLinked to original sources

bioRxiv2026

Long-term dysregulation of histone acetylation, BDNF expression, and the hippocampal transcriptome in adult rats exhibiting a depressive-like phenotype following repeated chlorpyrifos exposure

Epidemiological evidence indicates that occupational exposures to the organophosphate pesticide chlorpyrifos (CPF) in adults are associated with an increased risk for depression. In this study, we use a rat model of occupational-like CPF exposure associated with a chronic depressive phenotype to investigate underlying molecular mechanisms. Adult rats received CPF (5 mg/kg/day) for 21 days. When assessed three months later, blood and brain cholinesterase activity had returned to control levels despite the presence of depressive signs. Hippocampal tissue was collected at this endpoint for molecular analyses. Western blotting analysis showed significant upregulation of histone deacetylase protein levels of HDAC3 and HDAC5, whereas HDAC1 and HDAC2 were unchanged. HDAC5 regulates histone acetylation at the brain-derived neurotrophic factor (Bdnf) gene. We used chromatin immunoprecipitation to assay histone 3 lysine 9 acetylation (H3K9ac) occupancy at the Bdnf promoter IV. H3K9ac levels at the Bdnf promoter IV were significantly reduced in CPF rats, accompanied by a concomitant reduction in BDNF protein expression. Exploratory RNA-sequencing identified 100 significantly differentially expressed genes in CPF-exposed rats at a false discovery rate < 5%, including significant downregulation in genes such as insulin-like growth factor 2 (Igf2), fibroblast growth factor 14 (Fgf14), and slit guidance ligand 2 (Slit2) involved in neuronal growth, synaptic function, and axon guidance. Gene Ontology analysis revealed enrichment in pathways related to neurogenesis, neuronal projections, and myelination. Overall, this study indicates persistent epigenetic and transcriptional dysregulation associated with reduced hippocampal BDNF and alterations in neuronal plasticity-related pathways linked to a long-term depressive-like phenotype following CPF exposure.

pharmacology and toxicology↗

bioRxiv2026

EpiTADformer: A Transformer-Based Model for High-Resolution TAD Boundary Detection Using Epigenomic Signal Embeddings

The human genome is partitioned at different levels of 3D genome organization, with topologically associating domains (TADs) being among the most well-known and biologically important structures. TAD boundary disruption is associated with a wide range of diseases such as cancer, neurological and developmental disorders. Numerous methods have been developed to detect TAD boundaries from chromatin contact maps obtained with Hi-C technology. However, these methods are largely limited by the resolution of Hi-C data, typically 1 Kb to 100 Kb. In contrast, functional DNA loci, collectively referred to as epigenomic data, are profiled at a much higher resolution (100-200 bp for a typical ChIP-seq experiment). To improve the resolution of boundary detection, we hypothesize that the patterns of epigenomic signals associated with regions in proximity to TAD boundaries can serve as embeddings for these genomic regions, defining region similarity. These embeddings, along with their positional relationships, can be effectively modeled using deep learning to achieve more precise boundary prediction. We present EpiTADformer, a transformer-based model that takes as input transcriptional and histone modification signals of neighboring regions centered around TAD boundaries. We demonstrate that EpiTADformer outperforms feedforward neural network, convolutional neural network (CNN), and bidirectional long short-term memory (BiLSTM) network architectures. These results suggest the positional information of epigenomic signals surrounding TAD boundaries provides a strong predictive signal, enabling improved performance of the transformer model. Our findings highlight the potential of epigenomic signals to serve as region embeddings for refining the epigenomic language of TAD domains and 3D genome organization.

bioinformatics↗

bioRxiv2025

Beyond Blacklists: A Critical Assessment of Exclusion Set Generation Strategies and Alternative Approaches

Short-read sequencing data can be affected by alignment artifacts in certain genomic regions. Removing reads overlapping these exclusion regions, previously known as Blacklists, help to potentially improve biological signal. Tools like the widely used Blacklist software facilitate this process, but their algorithmic details and parameter choices are not always clearly documented, affecting reproducibility and biological relevance. We examined the Blacklist software and found that pre-generated exclusion sets were difficult to reproduce due to variability in input data, aligner choice, and read length. We also identified and addressed a coding issue that led to over-annotation of high-signal regions. We further explored the use of "sponge" sequences--unassembled genomic regions such as satellite DNA, ribosomal DNA, and mitochondrial DNA--as an alternative approach. Aligning reads to a genome that includes sponge sequences reduced signal correlation in ChIP-seq data comparably to Blacklist-derived exclusion sets while preserving biological signal. Sponge-based alignment also had minimal impact on RNA-seq gene counts, suggesting broader applicability beyond chromatin profiling. These results highlight the limitations of fixed exclusion sets and suggest that sponge sequences offer a flexible, alignment-guided strategy for reducing artifacts and improving functional genomics analyses.

bioinformatics↗

bioRxiv2021

Repeated exposure to chlorpyrifos is associated with a dose-dependent chronic neurobehavioral deficit in adult rats

Organophosphate (OP) chemicals include commonly used pesticides and also chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. While a chronic low-dose OP exposure does not produce acute cholinergic crises, epidemiological studies report long-term neuropsychiatric issues including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of a single, high-dose CPF or studied sub-chronic behavioral effects particularly the motor and cognitive effects of repeated low-dose CPF exposure. However, studies on chronic mood and depression-related morbidities following repeated sub-threshold CPF doses that would mimic occupationally-relevant OP exposures are lacking. Here, adult male rats were injected with CPF (1, 3, 5, or 10 mg/kg/d, s.c.) for 21-days. Dependent on the CPF dose, ChE activity was inhibited approximately 60-80% in the blood and about 20-50% in the hippocampus at 2-days after the end of CPF exposures. Following an 11-week washout period, CPF-treated rats exhibited a dose-dependent increase in signs of anhedonia (sucrose preference test), anxiety (open-field and elevated plus-maze), and despair (forced swim test) despite a complete recovery of ChE activity at this stage. We speculate that both cholinergic and non-cholinergic mechanisms could play a role in the development of chronic OP-related depressive outcomes. The proposed CPF exposure paradigm could provide an ideal model to further study molecular mechanisms underlying cause and effect relationships between environmental OP exposures and the development of chronic behavioral deficits.

pharmacology and toxicology↗

bioRxiv2020

Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging

Phase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. We examined published epigenome-wide studies of human blood and identified the SULT1A1 and UGT1A6 genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologs Sult1a1 and Ugt1a6 in liver tissue from mice aged 4-32 months obtained from the National Institute on Aging rodent tissue bank. Our sample shows significant loss of 5mC at Sult1a1, mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age at Sult1a1, but no change to histone 3 lysine 27 acetylation (H3K27ac). Sult1a1 gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant changes at Ugt1a6. We conclude that Sult1a1 expression is under epigenetic influence in normal aging and that this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug metabolizing pathways. In future, epigenetic biomarkers could prove useful to inform dosing in older adults.

genetics↗