期刊
CELL METABOLISM
卷 34, 期 9, 页码 1394-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2022.08.014
关键词
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资金
- NIH [U01-DK123716, 5UM-1DK126194, P30-DK19525]
- Functional Genomics Core of the Penn Diabetes Research Center [5U01-DK123594]
- Daniel B. Burke Endowed Chair for Diabetes Research
This study utilized various single-cell transcriptomic and 3D epigenomic technologies to analyze human pancreatic cells, revealing the cell-type-specific regulatory architecture of diabetes risk and highlighting the significant roles of alpha and acinar cells in diabetes pathogenesis.
Three-dimensional (3D) chromatin organization maps help dissect cell-type-specific gene regulatory pro-grams. Furthermore, 3D chromatin maps contribute to elucidating the pathogenesis of complex genetic dis-eases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell-type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differ-ential A/B (open/closed) chromatin compartmentalization, chromatin looping, and transcriptional factor -mediated control of cell-type-specific gene regulatory programs. We identified a total of 4,750 putative causal-variant-to-target-gene pairs at 194 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis.
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