Functional modules required for gene regulation are scattered throughout the entire human genome. Pervasive, ubiquitous RNA transcription generates interleaved domains of regulation. Proximal promoters regions (PPRs), for instance, are significantly enriched in transcription factor binding sites; PPRs are regulatory platform to integrate various cellular stimuli and are required to orchestrate gene expression.
These cis-regulatory domains, i.e., the PPRs, are interleaved with various classes of potentially regulatory RNAs. Transcriptional interference is known from long, it has originally been identified in bacterial genomes and yeast. The act of transcription itself leads to the occlusion of productive transcription factor/DNA binding and potentially interferes with pre-initiation complex assembly. In consequence the expression of affected genes is greatly impaired.
Given the wide spread nature of pervasive transcription and the fact that it is common to literally all kingdoms of life, we consider its main function might be the regulation of functionally interleaved domains, via the act of RNA transcription itself. This thought motivated the computational analysis of transcriptional interference within proximal promoters of human protein coding genes. For analysis we utilized capped and polyadenylated transcripts within eight different human cell lines. Effects caused by occluding RNA transcription on TF/DNA interaction were quantified.
Results revealed that TF-binding within PPRs of effected genes was severely impaired. These effects were also reflected in significantly lower DNA-binding affinities for occluded TFBSs compared to genome-wide controls. Reduced TF/DNA interactions ultimately correlated to diminished or sometimes even entirely abolished gene expression.
We consider that our analysis established new functional roles for small RNA transcription within proximal promoter regions of human genes. However, given that pervasive transcription is common to all kingdoms of life, it is suggestive that these results for the human genome are exemplary and that similar modes to regulate gene expression exist even in other gnomes.
Motivated by these initial findings we continue to explore potentially functional roles exerted by the sheer act of RNA expression on genome regulation in modes analogous to transcriptional interference.