Biology subjects

Jung, C.-H.

Publications and source records attributed to Jung, C.-H..

5 recordsLinked to original sources

bioRxiv2025

Prenatal Environmental Determinants of Aromatase Brain-Promoter Methylation in Cord Blood: Chemical, Airborne, Pharmacological, and Nutritional Factors

Aromatase, an enzyme encoded by the gene CYP19A1, plays central roles in neurodevelopment. In the brain, its function is to convert androgens into neuroestrogens, ensuring balanced hormonal signalling. Both animal experiments and human studies have shown that, in males, disruption of aromatase, either genetically or epigenetically, can increase symptoms of autism. Prenatal exposure to bisphenol A (BPA), a common plastic chemical, can increase levels of DNA methylation--a key epigenetic modification--at the brain-specific CYP19A1 promoter, P1.f, reducing CYP19A1 expression. However, the extent to which other neurodevelopmentally relevant environmental exposures influence P1.f methylation remains unclear. Here, in the Barwon Infant Study (BIS) birth cohort (N = 906), we analysed the association between 25 prenatal exposures (from five classes previously linked to neurodevelopmental outcomes: manufactured chemicals, air pollution, and pharmacological, nutrition and sunlight-related factors) and methylation of the CYP19A1 P1.f promoter using Weighted Quantile Sum (WQS) regression. We found that the WQS mixture index, a weighted combination of the prenatal exposures, was positively associated with higher P1.f methylation (Adjusted Mean Difference (AMD) = 0.712 (95% CI 0.11, 1.315), p = 0.021), indicating reduced brain aromatase activity. Prenatal exposures with the strongest contribution to the mixture effect included bisphenols (including BPA), reduced sunlight, household mould, phthalates, low folate intake, and air pollution. These findings highlight epigenetic modification of the aromatase gene as a biologically plausible, convergent mechanism through which multiple environmental risk factors for autism may exert effects.

genomics↗

bioRxiv2025

Prenatal DEHP plastic chemical exposure increases the likelihood of child autism and ADHD symptoms through epigenetic programming

Increasing evidence implicates prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting plastic chemical, in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the underlying mechanisms are poorly understood. Here we examined whether cord blood DNA methylation, a key epigenetic marker, mediates the association between prenatal DEHP exposure and ASD/ADHD symptoms in 847 children enrolled in the Barwon Infant Study. ASD and ADHD are complex phenotypes characterised by differences at the gene regulatory network and neuronal circuit level, where heterogeneous genetic and environmental risk factors converge. Accordingly, we employed a data-driven computational strategy that helped elucidate broader functional epigenetic signatures of ASD and ADHD elicited by DEHP exposure. This included (1) a methylation profile score for DEHP exposure (MPSDEHP), and (2) an analysis of co-methylated gene networks. Causal mediation analysis demonstrated that both MPSDEHP and a DEHP-associated network of co-methylated genes mediated the effect of DEHP exposure on increased ASD and ADHD symptoms at ages 2 and 4 years (proportion of effect mediated ranged from 0.21 to 0.80). The co-methylation network was enriched for neural cell-type markers, ASD risk genes (including FOXP1, SHANK2, and PLXNB1), and targets of endocrine receptors previously linked to DEHP (including targets of the estrogen receptor ER and the glucocorticoid receptor GR), providing biological plausibility. We validated key results in independent blood (n=66) and postmortem brain (n=40) DNA methylation datasets. These findings provide mechanistic evidence linking DEHP to ASD and ADHD symptoms and reinforce growing concerns regarding the risks of prenatal exposure.\n\nSignificanceExposure to endocrine-disrupting plastic chemicals has been linked to adverse neurodevelopment, but the underlying biological mechanisms remain unclear. We demonstrate that prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, increases autism and ADHD symptoms through alterations in DNA methylation, a key epigenetic regulator of gene activity. Using birth cohort data, we identify epigenetic signatures of prenatal DEHP exposure, including alterations in an endocrine-related co-methylation network enriched for neural cell-type markers and known autism-associated genes. These signatures mediate the effects of DEHP on autism and ADHD symptoms and are also associated with autism in external blood and postmortem-brain datasets, providing independent validation. This causal evidence further underscores concerns regarding the consequences of prenatal plastic-chemical exposure on the developing brain.

neuroscience↗

bioRxiv2025

The Landscape of Prostate Tumour Methylation

Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation, in part through modulation of epigenetic aging.

cancer biology↗

bioRxiv2022

Germline determinants of the prostate tumor genome

A persons germline genome strongly influences their risk of developing cancer. Yet the molecular mechanisms linking the host genome to the specific somatic molecular phenotypes of individual cancers are largely unknown. We quantified the relationships between germline polymorphisms and somatic mutational features in prostate cancer. Across 1,991 prostate tumors, we identified 23 co-occurring germline and somatic events in close 2D or 3D spatial genomic proximity, affecting 10 cancer driver genes. These driver quantitative trait loci (dQTLs) overlap active regulatory regions, and shape the tumor epigenome, transcriptome and proteome. Some dQTLs are active in multiple cancer types, and information content analyses imply hundreds of undiscovered dQTLs. Specific dQTLs explain at least 16.7% ancestry-biases in rates of TMPRSS2-ERG gene fusions and 67.3% of ancestry-biases in rates of FOXA1 point mutations. These data reveal extensive influences of common germline variation on somatic mutational landscapes.

cancer biology↗

bioRxiv2019

Smoking and blood DNA methylation: novel associations, replication of previous findings and assessment of reversibility

We conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N=3,327) and former (N=172) smoking. A comprehensive smoking index accounting for the bioactivity of smoking and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. We identified 4,496 cross-sectional associations at P<10-7, including 3,296 that were novel. We replicated the majority (90%) of previously reported associations for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR=63-86%). Consistent with this, we found wide-ranging estimates for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study provides evidence of many novel associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and indicates wide-ranging reversibility rates for smoking-induced methylation changes.

genomics↗