Transcriptional coordination between intergenic RNA polymerase II-bound regions and nearby genes reveals functional...

Recent studies have shown that RNA polymerase II (RNAPII) frequently occupies regions outside conventional promoters and gene bodies, forming intergenic RNAPII-bound regions (iRNAPII-BRs) that are actively transcribed and involved in gene regulation. We assessed the transcriptional activity of 181,547 iRNAPII-BRs from a genome-wide atlas and their impact on the expression of nearby gene in peripheral blood. The iRNAPII-BRs were often associated with structurally complex longer genes located in gene deserts. Their strongest transcriptional activity peaks occurred within 10 kb upstream from transcription start sites (TSSs), indicating a close regulatory link. Genes were grouped into six categories according to their transcriptional coordination with the nearest iRNAPII-BRs. Housekeeping genes tended to be transcribed independently, whereas blood tissue-specific genes were highly coordinated with iRNAPII-BR transcription. Genes with neuronal functions were frequently transcribed without active iRNAPII-BRs, suggesting basal promoter-driven expression with potential regulation by iRNAPII-BRs in response to blood-brain cross-talk cues. We found that 4507 iRNAPII-BRs were positively correlated with gene expression, whereas 793 were negatively correlated with gene expression implying a possible role in repression. The presence of transcription factor binding sites common to iRNAPII-BRs and promoters suggests a cooperative regulatory mechanism. Finally, we observed a differential expression of iRNAPII-BRs and nearby genes-ADRB2, CXCL8, SFN, and GPR3-in major depressive disorder, indicating that iRNAPII-BR-associated transcription may contribute to the pathophysiology of this disorder.