Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm.
Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm.
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DOI：
10.1172/jci153635
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发表时间：
2023-02-01
影响因子：
15.9
通讯作者：
Munshi, Nikhil V.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Samadrita;Kollipara, Rahul K.;Orquera-Tornakian, Gabriela;Goetsch, Sean;Zhang, Minzhe;Perry, Cameron;Li, Boxun;Shelton, John M.;Bhakta, Minoti;Duan, Jialei;Xie, Yang;Xiao, Guanghua;Evers, Bret M.;Hon, Gary C.;Kittler, Ralf;Munshi, Nikhil V.
全面的顺式调控景观对于准确的增强子预测和疾病变体定位至关重要。虽然顺式调控元件（CRE）资源存在于大多数组织和器官中，但许多罕见但功能重要的细胞类型仍然被忽视。尽管只占心脏细胞生物量的一小部分，但心脏传导系统（CCS）始终协调每一次维持生命的心跳。为了在全球范围内分析小鼠CCS顺式调控格局，我们对CCS组分特异性核进行了遗传标记，用于转座酶可及染色质测序（ATAC-Seq）分析的综合测定。因此，我们建立了一个全球CCS富集的CRE数据库，简称为CCS-ATAC，作为研究CCS范围和组件特定的调控功能的关键资源。利用转录因子（TF）基序构建CCS组分特异性基因调控网络（GRNs），我们确定并独立证实了几个特定的TF子网络。为了突出CCS-ATAC的功能重要性，我们还验证了许多CCS富集的增强子元件，并基于CCS单细胞RNA-Seq数据提出了基因靶点。此外，我们利用CCS-ATAC来改善与心律相关的现有人类变异的注释，并提名了一个由特定SNP失调的潜在增强子-靶对。总的来说，我们的研究结果建立了CCS调控纲要，确定了新的CCS增强子元件，并阐明了人类基因组变异和CCS组分特异性克雷斯之间的潜在功能关联。
Comprehensive cis-regulatory landscapes are essential for accurate enhancer prediction and disease variant mapping. Although cis-regulatory element (CRE) resources exist for most tissues and organs, many rare — yet functionally important — cell types remain overlooked. Despite representing only a small fraction of the heart’s cellular biomass, the cardiac conduction system (CCS) unfailingly coordinates every life-sustaining heartbeat. To globally profile the mouse CCS cis-regulatory landscape, we genetically tagged CCS component–specific nuclei for comprehensive assay for transposase-accessible chromatin–sequencing (ATAC-Seq) analysis. Thus, we established a global CCS-enriched CRE database, referred to as CCS-ATAC, as a key resource for studying CCS-wide and component-specific regulatory functions. Using transcription factor (TF) motifs to construct CCS component–specific gene regulatory networks (GRNs), we identified and independently confirmed several specific TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validated numerous CCS-enriched enhancer elements and suggested gene targets based on CCS single–cell RNA-Seq data. Furthermore, we leveraged CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominated a potential enhancer-target pair that was dysregulated by a specific SNP. Collectively, our results established a CCS-regulatory compendium, identified novel CCS enhancer elements, and illuminated potential functional associations between human genomic variants and CCS component–specific CREs.
影响因子：
2.7
作者：
Vedantham, Vasanth;Evangelista, Melissa;Huang, Yu;Srivastava, Deepak
通讯作者：
Srivastava, Deepak