小柯机器人

美国麻省理工学院Manolis Kellis研究组取得最新进展。他们通过整合表观基因组学研究人类疾病基因座的调控基因组环路。2021年2月3日国际知名学术期刊《自然》杂志发表了这一成果。

他们介绍了EpiMap，这是一份简编，包含800个样本的10,000个表观基因组图谱，他们利用这一图谱定义了染色质状态、高分辨率增强子、增强子模块、上游调节子和下游靶基因。他们使用此资源来注释与540个性状相关的30,000个基因位点，预测与性状相关的组织，富集组织增强子中的假定因果核苷酸变异体以及每个候选组织特异性靶基因。

他们将多因素性状分为具有特定功能丰富和疾病合并症模式的组织特异性贡献因素，并揭示了单因素单向性和多因素多向性基因座。得分最高的位点通常具有多个预测的驱动程序变异体，通过具有共同靶标基因，共同组织中的多个基因或多个基因和多个组织的多个增强子收敛，表明广泛的多效性。他们的结果证明了密集、丰富、高分辨率的表观基因组注释对于研究复杂性状的重要性。

研究人员表示，注释人类疾病的分子基础仍然是一项尚未解决的挑战，因为93％的疾病位点是非编码的，而基因调控注释则高度不完整。

附：英文原文

Title: Regulatory genomic circuitry of human disease loci by integrative epigenomics

Author: Carles A. Boix, Benjamin T. James, Yongjin P. Park, Wouter Meuleman, Manolis Kellis

Issue&Volume: 2021-02-03

Abstract: Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete1,2,3. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits4, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits.

DOI: 10.1038/s41586-020-03145-z

Source: https://www.nature.com/articles/s41586-020-03145-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html