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

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.