英国帝国理工学院的Jorge Ferrer研究团队报道了人类胰岛细胞的三维染色质结构，为2型糖尿病的遗传学研究提供了新的视角。2019年7月出版的国际知名学术期刊《自然—遗传学》发表了这一研究成果。

研究人员获取了人胰岛细胞的启动子Hi-C图谱。这将糖尿病相关的增强子与其通常相距数百kb远的靶基因联系起来。这个图谱也揭示了超过1300组由胰岛增强子、超级增强子以及活跃的启动子组成的3D区域，其中一些区域与葡萄糖依赖的活力相关。研究人员发现，这些区域的遗传突变会影响胰岛素分泌的遗传力，并且对这些区域的注释有助于预测变异带来的2型糖尿病风险。因此，人胰岛细胞3D染色质结构为解析2型糖尿病的全基因组关联分析提供了新的构架。

遗传学研究有望为2型糖尿病（T2D）的潜在发病分子机制提供新的见解。与2型糖尿病相关的变异通常位于组织特异性增强子簇或超增强子中。迄今为止，这些结构域被排列在线性基因组中的增强子簇所定义，但还没有其3D染色质结构的信息。此外，它们调控的靶基因也是未知的。

附：英文原文

Title: Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

Author: Irene Miguel-Escalada, Silvia Bons-Guarch, Ins Cebola, Joan Ponsa-Cobas, Julen Mendieta-Esteban, Goutham Atla, Biola M. Javierre, Delphine M. Y. Rolando, Irene Farabella, Claire C. Morgan, Javier Garca-Hurtado, Anthony Beucher, Ignasi Morn, Lorenzo Pasquali, Mireia Ramos-Rodrguez, Emil V. R. Appel, Allan Linneberg, Anette P. Gjesing, Daniel R. Witte, Oluf Pedersen, Niels Grarup, Philippe Ravassard, David Torrents, Josep M. Mercader, Lorenzo Piemonti, Thierry Berney, Eelco J. P. de Koning, Julie Kerr-Conte, Franois Pattou, Iryna O. Fedko, Leif Groop, Inga Prokopenko, Torben Hansen, Marc A. Marti-Renom, Peter Fraser, Jorge Ferrer

Issue&Volume:  Volume 51 Issue 7, July 2019

Abstract: Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.

DOI: 10.1038/s41588-019-0457-0

Source: https://www.nature.com/articles/s41588-019-0457-0