Mechanisms of Nascent Transcription in Cell Stress

Cells are constantly exposed to various types of stress, such as proteotoxic stress, oxidative stress, and hypoxia. Survival under these circumstances requires genome-wide reprogramming of transcription involving both induction and repression of genes. Induction of transcription under adverse conditions requires stress-responsive transcription factors, such as heat shock factors (HSFs) that drive gene activation in response to proteotoxic stress. Although cellular stress responses have been extensively studied, several key questions remain unanswered, including how transcriptional memory of previously experienced stress is encoded over mitotic divisions? Moreover, previous studies have focused on understanding the mechanisms of nascent transcription in heat-shocked cells, but studies utilizing other types of stress are lacking.

The results of this thesis show that exposure to an acute heat stress encodes a memory, which allows accelerated release of paused RNA polymerase II (Pol II) into transcriptional elongation during recurring stress. Chronic heat stress, in turn, reduces initiation of transcription at heat-inducible genes over mitotic divisions by increasing retention of Pol II within termination regions of genes. Furthermore, this thesis uncovers new roles for HSF1 and HSF2 as multi-stress responsive transcription factors that drive distinct transcription programs upon oxidative stress and heat shock. The results demonstrate that besides binding to gene promoters, HSF1 and HSF2 orchestrate transcription through stress specific enhancers, adding a new layer of complexity to HSF-mediated gene regulation. Lastly, this thesis investigates the mechanism of action for chaperone co-inducer BGP-15, which has provided beneficial effects for the treatment of proteinopathic diseases where HSF1-driven transcription is disrupted. BGP-15 is found to act as an HDAC inhibitor, promoting open chromatin structure and enhanced induction of target genes of HSF1. In conclusion, this thesis expands the knowledge of molecular mechanisms related to transcriptional memory of stress and the role of HSFs in the regulation of gene-enhancer networks.