人类皮下脂肪组织的单细胞DNA甲基化组和三维基因组图谱

Single-cell DNA methylome and 3D genome atlas of human subcutaneous adipose tissue.

作者信息

Chen Zeyuan Johnson, Das Sankha Subhra, Kar Asha, Lee Seung Hyuk T, Abuhanna Kevin D, Alvarez Marcus, Sukhatme Mihir G, Wang Zitian, Gelev Kyla Z, Heffel Matthew G, Zhang Yi, Avram Oren, Rahmani Elior, Sankararaman Sriram, Laakso Markku, Heinonen Sini, Peltoniemi Hilkka, Halperin Eran, Pietiläinen Kirsi H, Luo Chongyuan, Pajukanta Päivi

机构信息

Department of Computer Science, University of California, Los Angeles, CA, USA.

Department of Computational Medicine, University of California, Los Angeles, CA, USA.

出版信息

Nat Genet. 2025 Aug 20. doi: 10.1038/s41588-025-02300-4.

DOI:10.1038/s41588-025-02300-4

PMID:40835891

Abstract

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.

摘要

人类皮下脂肪组织（SAT）的细胞类型水平表观基因组景观尚未得到充分表征。在此，我们使用snm3C-seq阐明了跨SAT细胞类型的表观基因组景观。我们发现，SAT中的CG甲基化（mCG）在髓细胞中表现出明显的高甲基化，而在脂肪细胞以及脂肪干细胞和祖细胞中表现出低甲基化，这驱动了705,063个差异甲基化区域（DMR）中近一半的形成。此外，TET1和DNMT3A被确定为细胞类型水平mCG图谱的可能调节因子。全局mCG图谱和染色体分区都反映了SAT细胞类型谱系。值得注意的是，脂肪细胞表现出更多的短程染色体相互作用，形成复杂的局部三维基因组结构，调节包括脂肪生成在内的转录功能。此外，脂肪细胞DMR和A区室富含腹部肥胖全基因组关联研究（GWAS）变异和多基因风险，而髓细胞A区室富含炎症相关因素。总之，我们描绘了SAT单细胞水平的表观基因组景观，并将GWAS变异以及腹部肥胖和炎症的分区多基因风险与SAT表观基因组联系起来。