人脑各区域的等位基因特异性转录因子结合提供了对 eQTL 的机理认识

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Genome research Pub Date : 2024-08-16 DOI:10.1101/gr.278601.123
Ashlyn G Anderson, Belle A Moyers, Jacob M Loupe, Ivan Rodriguez-Nunez, Stephanie A Felker, James M.J. Lawlor, William E Bunney, Blynn G Bunney, Preston M Cartagena, Adolfo Sequeira, Stanley Watson, Huda Akil, Eric M Mendenhall, Gregory M Cooper, Richard M. Myers
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引用次数: 0

摘要

转录因子(TF)通过促进或破坏特定基因组位点转录启动机制的形成来调控基因表达。由于 TF 的占据部分是由 DNA 序列识别驱动的,因此遗传变异会影响 TF-DNA 关联和基因调控。为了确定影响人类脑组织中TF结合的变异,我们评估了两个供体9个脑区94个TF杂合变异的等位基因特异性结合(ASB)。利用分阶段基因组序列数据构建的图谱基因组,我们比较了每个脑区杂合变体等位基因之间的 ChIP-seq 信号,并确定了数千个至少对一种 TF 具有 ASB 的变体。ASB 的可重复性通过供体内部和供体之间独立实验的比较来衡量。我们发现,一般人群中较罕见的等位基因更经常导致 TF 结合力降低,而常见变异增加或减少结合力的可能性相同。基因组分析显示了TF的特异性效应,某些TF的ASB变体显示出更高的基因组改变发生率,以及纯化选择下变体的富集。值得注意的是,神经元特异性顺式调节元件(cCRE)显示出 ASB 变体的耗竭。我们从 GTEx 数据中发现了 2,670 个等位基因特异性基因在大脑中表达的 ASB 变异,并观察到随着 ASB 重要性的增加,eQTL 效应方向的一致性也在增加。这些结果为人类脑组织顺式调节变异的机理分析提供了宝贵而独特的资源。
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Allele specific transcription factor binding across human brain regions offers mechanistic insight into eQTLs
Transcription Factors (TFs) regulate gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Since TF occupancy is driven in part by recognition of DNA sequence, genetic variation can influence TF-DNA associations and gene regulation. To identify variants that impact TF binding in human brain tissues, we assessed allele specific binding (ASB) at heterozygous variants for 94 TFs in 9 brain regions from two donors. Leveraging graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signals between alleles at heterozygous variants within each brain region and identified thousands of variants exhibiting ASB for at least one TF. ASB reproducibility was measured by comparisons between independent experiments both within and between donors. We found that rarer alleles in the general population more frequently led to reduced TF binding, whereas common variation had an equal likelihood of increasing or decreasing binding. Motif analysis revealed TF-specific effects, with ASB variants for certain TFs displaying a greater incidence of motif alterations, as well as enrichments for variants under purifying selection. Notably, neuron-specific cis-regulatory elements (cCREs) showed depletion for ASB variants. We identified 2,670 ASB variants with prior evidence of allele-specific gene expression in the brain from GTEx data and observed increasing eQTL effect direction concordance as ASB significance increases. These results provide a valuable and unique resource for mechanistic analysis of cis-regulatory variation in human brain tissue.
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来源期刊
Genome research
Genome research 生物-生化与分子生物学
CiteScore
12.40
自引率
1.40%
发文量
140
审稿时长
6 months
期刊介绍: Launched in 1995, Genome Research is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies. New data in these areas are published as research papers, or methods and resource reports that provide novel information on technologies or tools that will be of interest to a broad readership. Complete data sets are presented electronically on the journal''s web site where appropriate. The journal also provides Reviews, Perspectives, and Insight/Outlook articles, which present commentary on the latest advances published both here and elsewhere, placing such progress in its broader biological context.
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