Transcription factor expression is the main determinant of variability in gene co-activity

Summary Co-activity scores for 343 GEUVADIS LCLs and ABC scores for 68 LCLs, of which 30 are contained in both. Project abstract Many genes are co-regulated and, when proximal, form domains of coordinated gene activity. However, the regulatory determinants of domain co-activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the regulatory processes underlying the activities of such domains and systematically quantify their effect sizes. We employ transcriptional decomposition to extract from RNA expression data an expression component related to co-activity revealed by genomic positioning. This strategy reveals close to 1,500 domains of co-activity, covering most expressed genes, of which the large majority are invariable across individuals. Focusing specifically on domains with high variation in co-activity reveals that neighboring genes contained within variable co-activity domains have a higher sharing of eQTLs, a higher variability in enhancer interactions, and a specific enrichment of binding by variably expressed transcription factors. Through careful quantification of the relative contributions of regulatory activities underlying co-activity, we find transcription factor expression levels to be the main determinant of gene co-activity, indicating that distal trans effects contribute more than local genetic variation to individual variation in co-activity domains. Included files Co_activity_scores_343_individuals.tsv.zip - Contains co-activity scores for included individuals. Columns include chromosome, bin, start, end and one column per individual containing the co-activity score. ABC_scores_68_individuals.tsv.zip - Contains ABC scores for included individuals. Columns include chromosome, start of putative enhancer region, end of putative enhancer region, name of putative enhancer region, target gene, TSS of target gene, LCL identifier, ABC score