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Genetic Basis, Quantitative Nature, and Functional Relevance of Evolutionarily Conserved DNA Methylation [CareGiver cohort]

ABSTRACT: DNA methylation (DNAm) is a key epigenetic mark that modulates regulatory elements and gene expression, playing a crucial role in mammalian development and physiological function. Despite extensive characterization of DNAm profiles across species, little is known about its evolutionary conservation. Here, we conducted a comparative epigenome-wide analysis of great apes to identify and characterize sequence- and methylation-conserved CpGs (MCCs). Using 202 DNAm arrays, alongside 6 matched genotype and 13 matched transcriptomic datasets, we identified 11,500 MCCs for which methylation was evolutionarily related to sequences of CpGs and methylation quantitative trait loci. MCCs were the most stable across healthy human tissues and exhibited weaker genetic associations than other CpGs. Moreover, MCCs showed minimal associations with demographic, environmental factors, and noncancer diseases, yet demonstrated stronger associations with certain cancers than other CpGs, particularly gastrointestinal cancers. Functional enrichment analysis revealed that genes associated with MCC methylation in cancer were enriched for cancer driver genes and canonical cancer pathways, highlighting a significant regulatory role for MCCs in tumorigenesis. Collectively, our findings reveal the extent of DNAm conservation in great ape evolution, its association with genetic conservation, and its relevance to human diseases. These integrative analyses offer evolutionary insights into epigenetic variation and its functional implications in human populations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281200 | GEO | 2024/11/11

REPOSITORIES: GEO

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Project description:Background: It is well-established that cancer treatment substantially increases risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions. Methods: We included 2,052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA. Results: By performing multiple treatment-specific EWAS, we identified 935 5’-cytosine-phosphate-guanine-3′ (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at epigenome-wide significance level (P<9×10-8). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (False-Discovery-Rate-Adjusted P<0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with 32.9% mediation effect and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA). Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.

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Genetic Basis, Quantitative Nature, and Functional Relevance of Evolutionarily Conserved DNA Methylation [CareGiver cohort]

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