美国宾夕法尼亚大学佩雷尔曼医学院Klaus H. Kaestner和Andrew D. Wells研究组合作绘制人类胰腺的三维 (3D)染色质图，揭示了T2D风险的谱系特异性调控结构。由2022年9月6日出版的《细胞—代谢》发表了这项成果。

为了了解糖尿病风险的细胞类型特异性调控结构，他们使用单细胞RNA-seq、单细胞ATAC-seq和高分辨率生成了人类胰腺腺泡、α和β细胞的转录组和3D表观基因组图谱已分类细胞的Hi-C。这些配置文件的比较揭示了差异A/B（开放/封闭）染色质区室化、染色质循环和转录因子介导的细胞类型特异性基因调控程序的控制。他们使用胰腺3D染色质图在194个2型糖尿病GWAS信号中确定了总共4,750个假定的因果变异到靶基因对。他们发现候选因果变异与其推定的靶效应基因之间的联系是细胞类型分层的，并强调了以前未被充分认识的α和腺泡细胞在糖尿病发病机制中的作用。

据介绍，3D染色质组织图有助于剖析细胞类型特异性基因调控程序。此外，3D染色质图通过将远端调控区域和遗传风险变异与其各自的靶基因联系起来，有助于阐明复杂遗传疾病的发病机制。

附：英文原文

Title: 3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk

Author: Chun Su, Long Gao, Catherine L. May, James A. Pippin, Keith Boehm, Michelle Lee, Chengyang Liu, Matthew C. Pahl, Maria L. Golson, Ali Naji, Struan F.A. Grant, Andrew D. Wells, Klaus H. Kaestner

Issue&Volume: 2022/09/06

Abstract: Three-dimensional (3D) chromatin organization maps help dissect cell-type-specific gene regulatory programs. Furthermore, 3D chromatin maps contribute to elucidating the pathogenesis of complex genetic diseases 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 differential 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.

DOI: 10.1016/j.cmet.2022.08.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00357-6