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Epigenome and Chromatin Analyses Uncover SPATC1L-COL6A as a Novel Causal Locus in Childhood Obesity

ABSTRACT: Childhood obesity is a major public health challenge, that increases the risk of comorbidities such as type 2 diabetes and cardiovascular disease, which collectively reduce life expectancy. Epigenetic mechanisms have been proposed as contributors to obesity-related long-term metabolic dysfunction. We performed DNA methylation profiling in whole blood from prepubertal children with obesity and normal weight controls, and identified 109 CpG sites associated with obesity. Two of these sites showed evidence of playing a causal role in mediating childhood obesity, as supported by two-sample Mendelian randomization test. Strikingly, both CpGs mapped within the same gene: Spermatogenesis and Centriole Associated 1 Like (SPATC1L). Further, we validated the causal CpGs in an independent clinical cohort. Together, these data suggest the SPATC1L locus might be a novel potential region playing a causal role on obesity development. To functionally confirm causality, we performed CRISPR/Cas9-mediated editing of these CpG sites. Their modification downregulated SPATC1L and neighbouring collagen genes (COL6A1, COL6A2), previously implicated in childhood obesity, and promoted higher lipid accumulation and insulin resistance in vitro. Following CpG editing, activating histone marks (H3K27Ac, H3K4me3) were reduced at the promoters of these genes, suggesting that these CpG sites regulate their expression through chromatin-mediated mechanisms. n summary, our study identifies the SPATC1L–COL locus as a novel causal region in childhood obesity and highlights mechanistic links between CpG methylation, histone modifications, deregulation of collagen gene expression, and metabolic dysfunction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329212 | GEO | 2026/05/04

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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Epigenome and Chromatin Analyses Uncover SPATC1L-COL6A as a Novel Causal Locus in Childhood Obesity

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