Identification of genomic enhancers through spatial integration of single-cell transcriptomics and epigenomics
Identification of genomic enhancers through spatial integration of single-cell transcriptomics and epigenomics
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DOI：
10.15252/msb.20209438
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发表时间：
2020-05-01
影响因子：
9.9
通讯作者：
Aerts, Stein
中科院分区：
文献类型：
--
作者：
Gonzalez-Blas, Carmen Bravo;Quan, Xiao-Jiang;Aerts, Stein
单细胞技术可以测量每个细胞中的染色质可及性和基因表达，但联合利用这两层来绘制真正的基因调控网络和增强子仍然具有挑战性。在这里，我们生成了果蝇眼天线盘的独立单细胞RNA-seq和单细胞ATAC-seq图谱，并在空间上将数据整合到一个虚拟的潜在空间中，该空间使用comap（使用伪时间排序的单细胞组学映射到空间轴）模拟二维组织的组织。为了验证空间预测的增强子，我们使用了大量的增强子报告系，并确定了85%的染色质可及性和增强子活性耦合的增强子。接下来，我们在虚拟空间中推断增强子与基因的关系，发现基因主要由多个（通常是冗余的）增强子调控。利用细胞类型特异性增强子，我们对大量衍生的染色质可接近性qtl的细胞类型特异性效应进行了反卷积。最后，我们发现普洛斯彼罗通过结合GGG基序驱动神经元分化。总之，我们提供了二维组织中基因调控的全面空间表征。
Single-cell technologies allow measuring chromatin accessibility and gene expression in each cell, but jointly utilizing both layers to map bona fide gene regulatory networks and enhancers remains challenging. Here, we generate independent single-cell RNA-seq and single-cell ATAC-seq atlases of the Drosophila eye-antennal disc and spatially integrate the data into a virtual latent space that mimics the organization of the 2D tissue using ScoMAP (Single-Cell Omics Mapping into spatial Axes using Pseudotime ordering). To validate spatially predicted enhancers, we use a large collection of enhancer-reporter lines and identify similar to 85% of enhancers in which chromatin accessibility and enhancer activity are coupled. Next, we infer enhancer-to-gene relationships in the virtual space, finding that genes are mostly regulated by multiple, often redundant, enhancers. Exploiting cell type-specific enhancers, we deconvolute cell type-specific effects of bulk-derived chromatin accessibility QTLs. Finally, we discover that Prospero drives neuronal differentiation through the binding of a GGG motif. In summary, we provide a comprehensive spatial characterization of gene regulation in a 2D tissue.