cis-regulation of RNA polymerase pausing

National Institute Of Environmental Health Sciences

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Abstract

The Transcriptional Responses in Disease group is a new lab at NIEHS having stated in late 2020. To explore the role of nucleic acid sequence and structure on the regulation of RNA polymerase pausing we have examined the association between guanine-rich sequences and RNA polymerase pausing in mitochondria. This work provides further evidence of the regulatory role of guanine quadruplexes in the control of transcription. In contrast to a model where quadruplexes form a barrier in front of an elongating polymerase, our initial finding show that quadruplexes form behind (5) paused mitochondrial RNA polymerase. Quadruplex stabilization is sufficient to pause the mitochondrial RNA polymerase, alter mitochondrial gene expression, and impair ATP production by the mitochondria. To study the dynamic regulation of RNA polymerase pausing we have turned to a hypertonic stress model. The sequence regulators of RNA polymerase pausing are shared between pause sites in the promoter and gene body of protein-coding genes in the nucleus, and at pause sites in the mitochondria. Despite sharing cis-regulators at pause sites in different locations in the genome, there is specificity to pause-release in response to different stimuli, including osmotic stress. We have identified a set of genes which exhibit pause-dependent gene induction following hypertonic stress in primary fibroblasts. As hypertonic stress is not part of normal fibroblast physiology, we are also generating corresponding data sets in collecting duct cells from the kidney.