小柯机器人

科学家绘制与疾病相关的全基因组增强子图谱
2021-04-11 18:03

美国麻省理工学院和哈佛大学的布罗德研究所Jesse M. Engreitz和Eric S. Lander团队合作取得最新进展。他们将全基因组增强子图谱将风险变异与疾病基因联系起来。相关论文于2021年4月7日发表在《自然》杂志上。

他们最近开发了接触活动(ABC)模型,以预测哪些增强子调节哪些基因,并使用CRISPR扰动在几种细胞类型中验证了该模型。他们应用这种ABC模型在131种人类细胞类型和组织中创建增强子-基因图,并使用这些图谱来解释全基因组关联研究(GWAS)变体的功能。在72种疾病和复杂性状中,ABC将5,036个GWAS信号与2,249个独特基因相关联,其中一类包括577个基因,这些基因似乎通过作用于不同细胞类型的增强子变异影响多种表型。

在炎症性肠病(IBD)中,在特定的细胞类型(例如树突状细胞)中,因果变体在预测的增强子中富集了20倍以上,并且ABC在将非编码变体连接到靶标基因上比其他调节方法具有更高的精确度。这些变体功能图揭示了一种增强子,其包含IBD风险变体并调节PPIF的表达,从而改变巨噬细胞中线粒体的膜电位。

他们的研究揭示了基因组调控的原理,确定了影响IBD的基因,并提供了一种资源和可推广的策略,以将常见疾病的风险变异体与其分子和细胞功能联系起来。

研究人员表示,GWAS已鉴定出数千个与人类疾病和复杂性状相关的非编码基因座,每个基因座都可以揭示对疾病机制的见解。许多潜在的因果变异可能会影响增强子,但人们缺乏增强子及其靶基因的准确图谱来解释此类变异。

附:英文原文

Title: Genome-wide enhancer maps link risk variants to disease genes

Author: Joseph Nasser, Drew T. Bergman, Charles P. Fulco, Philine Guckelberger, Benjamin R. Doughty, Tejal A. Patwardhan, Thouis R. Jones, Tung H. Nguyen, Jacob C. Ulirsch, Fritz Lekschas, Kristy Mualim, Heini M. Natri, Elle M. Weeks, Glen Munson, Michael Kane, Helen Y. Kang, Ang Cui, John P. Ray, Thomas M. Eisenhaure, Ryan L. Collins, Kushal Dey, Hanspeter Pfister, Alkes L. Price, Charles B. Epstein, Anshul Kundaje, Ramnik J. Xavier, Mark J. Daly, Hailiang Huang, Hilary K. Finucane, Nir Hacohen, Eric S. Lander, Jesse M. Engreitz

Issue&Volume: 2021-04-07

Abstract: Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer–gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.

DOI: 10.1038/s41586-021-03446-x

Source: https://www.nature.com/articles/s41586-021-03446-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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