Closing the gap: a roadmap to single-cell regulatory genomics

Abstract

Studying the spatiotemporal control of gene regulatory networks at the single-cell level is still a challenge, yet it is key to understanding the mechanisms driving cellular identity. In their recent study, Aerts and colleagues (González-Blas et al, 2020) develop a new strategy to spatially map and integrate single-cell transcriptome and epigenome profiles in the Drosophila eye-antennal disc and to deduce in each cell precise enhancer-to-gene activity relationships. This opens a new era in the transcriptional regulation field, as it allows extracting from each of the thousands of cells forming a tissue the critical features driving their identity, from enhancer sequences to transcription factors to gene regulatory networks.

Figure 1. A roadmap to single‐cell regulatory genomics

González‐Blas et al generated independent single‐cell RNA‐seq and single‐cell ATAC‐seq atlases of the Drosophila eye‐antennal disc and spatially integrated them using a virtual latent space that mimics the organization of the 2D tissue. Predicted enhancers were validated using the Janelia Flylight collection of enhancer‐reporter lines, which confirmed the coupling of chromatin accessibility and enhancer activity. Using random forest regression models, enhancer‐to‐gene relationships were calculated in each cell, which revealed that gene regulation is highly redundant and each gene is controlled by multiple enhancers. The single‐cell information was finally used to deconvolute cell‐type specific effects of bulk derived chromatin accessibility data, which identified new motifs and TFs active in specific cell types of the eye‐imaginal disc (Several elements shown in this Figure have been reused from González‐Blas et al, 2020, including the virtual enhancer activity map, the confocal image showing the enhancer activity in the eye‐antennal disc and the example of the chromatin accessibility QTL, Topic 24).