Nascent RNA variation reveals architecture and interactions of transcribed regulatory elements

Active transcriptional regulatory elements are bidirectionally transcribed, the level of transcription correlating with regulatory activity. Using capped nascent RNA sequencing (PRO-cap) in 69 human lymphoblastoid cell lines, we identify 87,826 transcribed transcriptional regulatory elements (tTREs) and thousands of genetic variants that associate with tTRE transcription. Many of these variants associate with gene expression and are enriched at specific positions – central transcription factor (TF) binding sites or surrounding transcription start sites – consistent with a dual-hub tTRE architecture. Additionally, co-expression analyses reveal interactions between tTREs. We find evidence of TFs influencing mid- to long-range interactions and of strand-dependent cooperativity at closely-spaced tTREs. Identification and quantification of transcriptional activity at transcriptional regulatory elements (using PRO-cap) across YRI population.