Identification of genomic enhancers through spatial integration of single‐cell transcriptomics and epigenomics. Issue 5 (19th May 2020)

• Record Type: Journal Article
• Authors: Bravo González‐Blas, Carmen; Quan, Xiao‐Jiang; Duran‐Romaña, Ramon; Taskiran, Ibrahim Ihsan; Koldere, Duygu; Davie, Kristofer; Christiaens, Valerie; Makhzami, Samira; Hulselmans, Gert; de Waegeneer, Maxime; Mauduit, David; Poovathingal, Suresh; Aibar, Sara; Aerts, Stein
• Is Part Of: Molecular systems biology. Volume 16:Issue 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-19
• Subjects: enhancer detection -- eye‐antennal disc -- gene regulation -- single‐cell omics -- spatial integration; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20209438
• Languages: English
• ISSNs: 1744-4292

Abstract

Abstract: 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 ~ 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. Synopsis: In this study, scRNA‐seq and scATAC‐seq atlases of the Drosophila eye‐antennal disc are spatially integrated. A combination of enhancer‐reporter assays, machine learning, caQTL analysis and genetic perturbations identifies core regulatory mechanisms. A virtual map is created to spatially integrate independent single‐cell RNA‐seq and single‐cell ATAC‐seq data from the Drosophila eye‐antennal disc. Spatial comparison of chromatin accessibility and enhancer activity reveals that accessibility and activity are coupled for ˜ 85% of the accessible regions. Enhancer‐to‐gene links inferred from the spatial map suggest that genes are mostly regulated by multiple, often redundant, enhancers. Single‐cell omics, cell‐type specific caQTL analysis and perturbation experiments show that an enriched GGG motif in photoreceptors enhancers is bound by the transcription factor Prospero. Abstract : In this study, scRNA‐seq and scATAC‐seq atlases of the Drosophila eye‐antennal disc are spatially integrated. A combination of enhancer‐reporter assays, machine learning, caQTL analysis and genetic perturbations identifies core regulatory mechanisms.