Fig. 2: miRNAs, transcription factors and nuclear organization define covariations.

a miRNA targets tend to covary. Covariations enrichment scores (CES) for the top 200, 300, and 500 ranked miRNA targets according to TargetScan, for the seven highest expressed conserved miRNA and for a control set for comparison for 500 randomly selected targets. p-values refer to respective controls. b miRNA target covariations occur post-transcriptionally and are miRNA-dependent. Enrichment in sets of the top 200 ranked miRNA targets in parental cells (WT) and Drosha KO cells, that are void of canonical miRNAs. Enrichments are color coded for exonic reads, representing post-transcriptional regulation (orange) or intronic reads representing transcriptional regulation (yellow). c Covarying genes are enriched for shared miRNA targeting. Reverse covariation enrichment shows the log2 ratio between covariations that share a common miRNA and permuted covariations that share a common miRNA. d Transcription factor targets are enriched for gene covariations. Enrichment in sets of the top 200, 300, and 500 transcription factor targets, for 145 transcription factors profiled with ChIP-seq. Control for comparison is shown for 500 randomly selected targets. p-values refer to respective controls. e Transcription factor target covariations are transcriptional and miRNA-independent. Enrichment in sets of the 200 ranked transcription factor targets in parental cells (WT) and Drosha KO cells. Enrichments are color coded for exonic reads (dark green) or intronic reads (light green). f Covarying genes are enriched for shared transcription factor targeting (figure similar to c). g Genes that are in close nuclear proximity and locate to the same chromosome are enriched for covariations. The range categories are mutually exclusive, for instance pairs of genes that are <5 MB apart are not included in the <25 MB category. h Gene regions that are in close nuclear proximity and locate to different chromosomes are enriched for covariations. Since relatively few intrachromosomal Hi-C contacts were identified, we here used a less stringent criteria (p-value <0.05) cut-off to robustly identify significant covariations. i Circos plot showing significant covariations and Hi-C contacts for chromosomes 15, 17, and 19. Significantly covarying gene pairs are connected by a light blue line. Inter-chromosomal Hi-C contacts are shown as gray lines. j Covarying genes are enriched for interchromosomal Hi-C contacts (figure similar to c). a, b, d, e All p-values represent two-sided independent two-group t-tests between targets sets and respective controls (see “Methods” section).