Building gene regulatory networks from single-cell ATAC-seq and RNA-seq using linked self-organizing maps

​Rapid advances in single-cell assays have outpaced methods for analysis of those data types. Different single-cell assay show extensive variation in sensitivity and signal to noise levels. In particular, single-cell ATAC-seq generates extremely sparse and noisy datasets. Existing methods developed to analyze this data require cells amenable to pseudo-time analysis or require a dataset with drastically different cell-types. We describe a novel approach using self-organizing maps (SOM) to link scATAC-seq and scRNA-seq data that overcomes these and can be generate draft regulatory networks. Our SOMatic software package generates chromatin and gene expression SOMs separately and combines them using a linking function. We applied SOMatic on a mouse pre-B cell differentiation time-course using controlled Ikaros over-expression to recover temporal gene ontology enrichments, identify motifs in genomic regions showing similar single-cell profiles, and generate a gene regulatory network that both recovers known interactions and predicts new Ikaros targets during the differentiation process. The ability of linked SOMs to detect emergent properties from multiple types of highly-dimensional genomic data with very different signal properties opens new avenues for integrative analysis of single-cells.

DOI: 10.1101/438937

Building gene regulatory networks from single-cell.pdf