A Bidirectional Non-Coding RNA Promoter Mediates Long-Range Gene Expression Regulation

Recent evidence suggests that human gene promoters display gene expression regulatory mechanisms beyond the typical single gene local transcription modulation. In mammalian genomes, genes with an associated bidirectional promoter are abundant; bidirectional promoter architecture serves as a regulatory hub for a gene pair expression. However, it has been suggested that its contribution to transcriptional regulation might exceed local transcription initiation modulation. Despite their abundance, the functional consequences of bidirectional promoter architecture remain largely unexplored. This work studies the long-range gene expression regulatory role of a long-non-coding RNA gene promoter using chromosome conformation capture methods. We found that this particular bidirectional promoter contributes to distal gene expression regulation in a target-specific manner by establishing promoter-promoter interactions. In particular, we validated that bidirectional promoter is contacting multiple gene promoter elements, including BBX promoter, upon loss-of-function assays reduced bidirectional-promoter interactions associated with increased BBX promoter-enhancer and augmented gene expression. Moreover, long-range regulatory functionality is not directly dependent on its associated non-coding gene pair expression levels. To investigate transcriptome-wide changes upon removal of a long-non-coding-RNA bidirectional promoter associated to DUBR and LINC00882 transcription start sites (BBQ element), we created a CRISPR-Cas9 model on K562 cells