Overview
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Key numbers
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- 73 from N=32 individuals from Madre de Dios, Peru. Madre de Dios has high artisanal and small-scale gold mining activity,
- 74 which results in high MeHg exposure to nearby residents. We compared DNA methylation in N=16 individuals with high
- 75 (>10 µg/g) vs. N=16 individuals with low (<1 µg/g) total hair mercury (a proxy for methylmercury exposure), matched on age
- 127 in MeHg exposure due to nearby artisanal and small-scale gold mining2 (Table 1). This approach has two distinct strengths.
- 170 BeadChip (N=2,286 from 6 studies), Infinium 450K BeadChip (N=1,866 samples from 20 studies from Gene Expression
- 171 Omnibus or The Cancer Genome Atlas), and Reduced Representation Bisulfite Sequencing data (N=232 samples of
- 179 differentially methylated sites ranks based on three criteria: 1) the difference in mean methylation, 2) the quotient in mean
- 183 computed using: 1) the mean differences in means across all sites in a region between high and low MeHg groups, 2) the
- 184 mean of quotients in mean methylation, and 3) the combined p-value from all site p-values in the region. Each region was
- 187 computed similarly to differential methylation on the region level, using the mean of variances, log-ratio of the quotient of
- 199 long-range qPCR assay that evaluates whether DNA lesions are present that can halt or slow DNA polymerase progression
- 214 We measured mtDNA CN using an established short-range, real-time, standard curve-based qPCR assay that is specific
- 226 methylation (p <0.05). Tables with complete data are available in the Gene Expression Omnibus (GSE207443).
- 233 differentially variable DNA methylation (p <0.05). Tables with complete data are available in the Gene Expression Omnibus
- 243 best ranking regions, all with p≤0.01) (Supplemental Tables S1-2, selected terms in Table 2). We observed 46 BP GO
- 245 groups (using a cutoff of combined rank among the 1000 best ranking regions, all with p≤0.01) (Supplemental Tables S3-
- 247 hypervariable DNA methylation between exposure groups, using the same cutoffs (Supplemental Tables S5-6, selected
- 248 terms in Table 4), as well as 33 terms in gene regions and 43 terms in promoter regions with hypovariable DNA methylation
- 249 between exposure groups (Supplemental Tables S7-8). Most enriched GO terms were related to immune response, with
- 250 a particular focus on the innate immune response/inflammation (Tables 2-4, Supplemental Tables S1-S8).
- 290 genes and promoters in high MeHg- vs. low MeHg-exposed Peruvians reflect innate immune response activation (Table 2,
- 291 Supplemental Tables S1-2). Loss of DNA methylation in promoters and genes are generally associated with gene
- 294 prostaglandins84 (Tables 2 and 4, Supplemental Tables S1-S2). In addition, we observed evidence of immune responses
- 295 in several T- and B-cell subtypes (Tables 2 and 4, Supplemental Tables S1-S2). Both T-cells and B-cells develop effector
- 303 tumor necrosis factor a (TNFa), macrophage-activating interferon g (IFN g)) (Tables 2 and 4, Supplemental Tables S1-S2
- 305 13), B-cell isotope switching) (Supplemental Tables S1-S2 and S4-S5). Importantly, the Th1 response is most evident in
- 306 our GO enrichments of differential mean DNA methylation (Tables 2 and 3, Supplemental Tables S1-S4) and the Th2
- 307 signal is clearest in GO enrichments of hypervariable DNA methylation (Table 4, Supplemental Tables S4-S5). These
- 318 show increases in all three of these signals (Tables 2 and 4, Supplemental Tables S1-S4), indicating an environment
- 323 decreased IL-7 signaling (Table 3, Supplemental Tables S3-S4), are consistent with an expanded pool of autoreactive
- 326 marginal zone B cell differentiation (Table 2), which is consistent with activation of the target genes of these promoters.
- 333 differential DNA methylation signatures of response (Supplemental Tables S5-S6).
- 338 cells (Fig. 1A-B, Supplemental Figs. S3-S13). Broadly, hematopoiesis generates a range of blood cell types, including red
- 344 white blood cell differentiation94,95. In the presence of STAT3 (Fig. 1A) and interleukin-3 signaling (Supplemental Table
- 349 are supported by an increase in monocyte cell proportion (on average, 6% in high MeHg vs. 4% monocytes in low MeHg
- 392 is enriched in hypomethylated genes (in high vs. low MeHg-exposed individuals) (Supplemental Table S1). In leukocytes,
- 432 hypermethylation of the RIG-1 signaling pathway (Supplemental Table S4) through which DAMPs trigger innate immune
- 439 well as hypervariable promoter DNA methylation in pathways involved in ROS production and response (Table 4), strongly
- 449 dedifferentiation involving in phenotypic switching” (GO:0090678) (Supplemental Tables S5-S6).
- 455 high MeHg group reside in indigenous communities in the Madre de Dios region (Table 1), because the highest MeHg
- 477 Data sharing. We have deposited raw data files and sample phenotype data, as well as tables containing differential DNA
- Table 1. Descriptive statistics of age- and sex-matched study participants with either high (>10 µg/g) or low (<1 µg/g)
Methods (brief)
- 140 Sample population
- 153 For both DNA methylation and mtDNA analyses, 8.5 mL of whole blood was collected in PAXgene Blood DNA Tubes
- 157 were stored at -80°C until DNA was isolated. For DNA isolation, the frozen whole blood samples were thawed in a 37°C
- 164 blood samples using the estimateCellCounts function in the minfi package58 and estimated pairwise associations between
- 170 BeadChip (N=2,286 from 6 studies), Infinium 450K BeadChip (N=1,866 samples from 20 studies from Gene Expression
- 171 Omnibus or The Cancer Genome Atlas), and Reduced Representation Bisulfite Sequencing data (N=232 samples of
- 172 German origin). Training datasets include majority European samples (datasets are listed at
- 197 (Invitrogen 15612-013) as described63. Samples were then diluted to 3 ng/μL in 0.1X TE buffer for use in long amplicon
- 200 during PCR amplification. This assay’s primers amplify an 8.9 kb fragment from mtDNA. Samples with greater loads of DNA
- 477 Data sharing. We have deposited raw data files and sample phenotype data, as well as tables containing differential DNA
- 52 Arai, Y. et al. Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human
- 103 Wadman, I. et al. Specific in vivo association between the bHLH and LIM proteins implicated in human T cell
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