Abstract IA10: Regulating transcription elongation at stimulus responsive genes

Abstract

Abstract The majority of mammalian protein-coding genes display transcription in both sense and anti-sense directions. At such bidirectional promoters, Pol II has been shown to initiate transcription and undergo promoter-proximal pausing near both the sense-strand mRNA transcription start site (TSS) and from within the upstream region in the anti-sense direction. This enigmatic, dual promoter structure raises fundamental questions about the specificity, purpose and regulation of upstream anti-sense transcription. Interestingly, transcription in the anti-sense direction is generally non-processive and creates short, unstable non-coding RNAs (ncRNAs). Intriguingly, many distal enhancer regions display bidirectional transcription and generate short unstable ncRNAs, raising parallels between enhancers and anti-sense promoters near protein-coding genes. Importantly, enhancers and upstream anti-sense promoters show exquisite cell type specificity in their location and activity, suggesting key roles in establishing cell state and behavior. Further, perturbation of either transcription or chromatin structure at such non-coding loci has been implicated in the development of cancer and disease, with a profound impact on maintenance of cell state and responsiveness to stimuli. These recent findings raise a number of intriguing questions about the communication between promoters and non-coding loci. Our work has recently defined a mechanism through which upstream anti-sense transcription impacts stimulus-responsive gene expression. Specifically, we found that the distance between sense and anti-sense TSSs at bidirectional promoters strongly influences activation of pro-inflammatory genes in macrophages. We discovered that anti-sense TSSs organize chromatin structure, creating a region of open chromatin between bidirectional TSSs that is optimal for recruitment of the transcription machinery and signal-dependent transcription factors like NF-kB. Further, we discovered that key inflammatory genes possess enhancer-like histone modifications around the anti-sense TSS, and that this characteristic selectively marks genes that are highly activated upon immune stimulation. Citation Format: Karen Adelman, Benjamin S. Scruggs, Telmo Henriques, Adam Burkholder, David C. Fargo. Regulating transcription elongation at stimulus responsive genes. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA10.