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利用长程染色质相互作用重建血液代谢组和基因型。

Reconstructing the blood metabolome and genotype using long-range chromatin interactions.

作者信息

Fadason Tayaza, Schierding William, Kolbenev Nikolai, Liu Jiamou, Ingram John R, O'Sullivan Justin M

机构信息

The Liggins Institute, The University of Auckland, Auckland, New Zealand.

Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.

出版信息

Metabol Open. 2020 Mar 19;6:100035. doi: 10.1016/j.metop.2020.100035. eCollection 2020 Jun.

DOI:10.1016/j.metop.2020.100035
PMID:32812909
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7424797/
Abstract

BACKGROUND

-Maintenance of tight controls on circulating blood metabolites is crucial to normal, healthy tissue and organismal function. A number of single nucleotide polymorphisms (SNPs) have been associated with changes in the levels of blood metabolites. However, the impacts of the metabolite-associated SNPs are largely unknown because they fall within non-coding regions of the genome.

OBJECTIVE

-We aimed to identify genes and tissues that are linked to changes in circulating blood metabolites by characterizing genome-wide spatial regulatory interactions involving blood metabolite-associated SNPs.

METHOD

-We systematically integrated chromatin interaction (Hi-C), expression quantitative trait loci (eQTL), gene ontology, drug interaction, and literature-supported connections to deconvolute the genetic regulatory influences of 145 blood metabolite-associated SNPs.

FINDINGS

-We identified 577 genes that are regulated by 130 distal and proximal metabolite-associated SNPs across 48 different human tissues. The affected genes are enriched in categories that include metabolism, enzymes, plasma proteins, disease development, and potential drug targets. Our results suggest that regulatory interactions in other tissues contribute to the modulation of blood metabolites.

CONCLUSIONS

-The spatial SNP-gene-metabolite associations identified in this study expand on the list of genes and tissues that are influenced by metabolic-associated SNPs and improves our understanding of the molecular mechanisms underlying pathologic blood metabolite levels.

摘要

背景

对循环血液代谢物进行严格控制对于正常、健康的组织和机体功能至关重要。许多单核苷酸多态性（SNP）与血液代谢物水平的变化有关。然而，与代谢物相关的SNP的影响在很大程度上尚不清楚，因为它们位于基因组的非编码区域内。

目的

我们旨在通过表征涉及血液代谢物相关SNP的全基因组空间调控相互作用，来识别与循环血液代谢物变化相关的基因和组织。

方法

我们系统地整合了染色质相互作用（Hi-C）、表达定量性状位点（eQTL）、基因本体、药物相互作用以及文献支持的联系，以剖析145个血液代谢物相关SNP的遗传调控影响。

结果

我们在48种不同的人体组织中鉴定出577个受130个远端和近端代谢物相关SNP调控的基因。受影响的基因富集于包括代谢、酶、血浆蛋白、疾病发展和潜在药物靶点等类别中。我们的结果表明，其他组织中的调控相互作用有助于调节血液代谢物。

结论

本研究中确定的空间SNP-基因-代谢物关联扩展了受代谢相关SNP影响的基因和组织列表，并增进了我们对病理性血液代谢物水平潜在分子机制的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/089def792990/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/ab1acf0a3ce8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/a14ad26a61e7/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/10e942cef514/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/63b1d614e16f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/765ab41c361e/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/089def792990/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/ab1acf0a3ce8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/a14ad26a61e7/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/10e942cef514/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/63b1d614e16f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/765ab41c361e/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b81f/7424797/089def792990/gr6.jpg

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