biostudies-literatureChen ZJNovo Nordisk Fonden (Novo Nordisk Foundation)NIDDK NIH HHSNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)NHGRI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)2238-2249https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373012biostudies-literatureUnknown57(9)The cell-type-level epigenomic landscape of human subcutaneous adipose tissue (SAT) is not well characterized. Here, we elucidate the epigenomic landscape across SAT cell types using snm3C-seq. We find that SAT CG methylation (mCG) displays pronounced hypermethylation in myeloid cells and hypomethylation in adipocytes and adipose stem and progenitor cells, driving nearly half of the 705,063 differentially methylated regions (DMRs). Moreover, TET1 and DNMT3A are identified as plausible regulators of the cell-type-level mCG profiles. Both global mCG profiles and chromosomal compartmentalization reflect SAT cell-type lineage. Notably, adipocytes display more short-range chromosomal interactions, forming complex local 3D genomic structures that regulate transcriptional functions, including adipogenesis. Furthermore, adipocyte DMRs and A compartments are enriched for abdominal obesity genome-wide association study (GWAS) variants and polygenic risk, while myeloid A compartments are enriched for inflammation. Together, we characterize the SAT single-cell-level epigenomic landscape and link GWAS variants and partitioned polygenic risk of abdominal obesity and inflammation to the SAT epigenome.Nature geneticsSingle-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.PMC12373012R01 DK132775R01 HG010505NNF20OC0060547NNF17OC0027232NNF10OC1013354R01DK132775R01HG010505R01HL170604R01 HL170604Pietilainen KHAlvarez MHeinonen SPeltoniemi HGelev KZPajukanta PSankararaman SLuo CKar AHalperin EHeffel MGZhang YSukhatme MGChen ZJLee SHTWang ZAvram ORahmani ELaakso MAbuhanna KDDas SSfalseSingle-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.The cell-type-level epigenomic landscape of human subcutaneous adipose tissue (SAT) is not well characterized. Here, we elucidate the epigenomic landscape across SAT cell types using snm3C-seq. We find that SAT CG methylation (mCG) displays pronounced hypermethylation in myeloid cells and hypomethylation in adipocytes and adipose stem and progenitor cells, driving nearly half of the 705,063 differentially methylated regions (DMRs). Moreover, TET1 and DNMT3A are identified as plausible regulators of the cell-type-level mCG profiles. Both global mCG profiles and chromosomal compartmentalization reflect SAT cell-type lineage. Notably, adipocytes display more short-range chromosomal interactions, forming complex local 3D genomic structures that regulate transcriptional functions, including adipogenesis. Furthermore, adipocyte DMRs and A compartments are enriched for abdominal obesity genome-wide association study (GWAS) variants and polygenic risk, while myeloid A compartments are enriched for inflammation. Together, we characterize the SAT single-cell-level epigenomic landscape and link GWAS variants and partitioned polygenic risk of abdominal obesity and inflammation to the SAT epigenome.2025-01-01T00:00:00Z2025 Sep2026-06-03T07:09:56.309Z2026-04-25T03:22:26.99ZS-EPMC123730124083589110.1038/s41588-025-02300-4