Fig. 2: DNA methylation-target gene associations in human adipocytes.

a–c Locus plots of sentinel 5mC sites (diamond) and their predicted target effector genes (dark grey). a Methylation at cg01558212 in the SATB2 promoter was associated with SATB2 and SATB2-AS1 gene transcription (subcutaneous). b Methylation at two sites, cg11307296 and cg13390388, within distinct functional loops in human adipocyte promoter capture HiC connectivity maps, was associated with transcription of the adipocyte browning/beigeing gene EBF2 (subcutaneous). c Methylation at cg03779326 was associated with transcription of RPN1 but not other putative target genes within a shared human adipocyte TAD (visceral). Presented as %-difference in methylation between obese cases and controls, annotated by UCSC CpG island (CGI) and Roadmap adipose (E063) and adipocyte (E025) chromatin states. d Frequency of sentinel methylation-expression associations at FDR < 0.01 according to target gene assignment method. Genic: sentinel in promoter, 5/3ʹUTR or exon. Functional: intronic/intergenic sentinel sharing functional interaction with distal target gene. TAD: intronic/intergenic sentinel and distal target gene(s) within shared human adipocyte topologically associated domain. Adi C-HiC: human adipocyte promoter capture Hi-C interaction. Other C-HiC: promoter capture Hi-C interaction in another human tissue. eRNA coexprN: co-expression of distal eRNA and proximal promoter RNA. eQTLs: Association of distal SNP with proximal promoter expression. TF coexprN: TF binding in distal site (ChIP-seq) and TF-target gene co-expression. 1 to >5 assocN: Number of sentinel-target gene associations in shared TAD. e Subcutaneous sentinel-target gene associations at FDR < 0.01 grouped by target gene annotation method, coloured by adipocyte chromatin state (Roadmap E025). Left panel: distance to TSS and -log10 pvalue according to direction of effect, and sentinel density distribution. Right panel: frequencies of observed associations compared to the null background (sentinel-gene associations at FDR > 0.01). Fold change: log2 fold change in gene expression for each unit change in methylation. f Enriched pathways and genesets at P < 0.001 (Empirical, one-sided) based on the nearest cis−gene to each 5mC sentinel in subcutaneous and visceral adipocytes. Bar represents fold change of observed compared to mean expected frequency, number is the observed gene counts, in each pathway/geneset. All methylation-expression analyses were carried out using mixed-effects linear regression in combined adipocyte samples.