Understanding mechanisms that regulate transcription genome-wide as cells respond to stress
Programmed responses to external stimuli and stress allow cells to adapt to changing environmental conditions, and are critical for cellular survival. mRNA transcription by RNA polymerase II (Pol II) is rapidly regulated in response to many different types of cellular stress, including heat shock. In response to heat shock in human cells, several hundred genes are rapidly activated, while several thousand genes are rapidly repressed. We take advantage of high-throughput sequencing approaches to investigate the mechanisms that control genome-wide programs of mixed transcriptional responses (i.e. activation and repression).
Most recently we have focused our studies on how the termination of mRNA transcription is altered by heat shock. In the past several years, several studies in mammalian cells revealed that Pol II transcriptional termination is disrupted during different types of cellular stress, including heat shock. However, the mechanisms by which this occurs are not understood. Disruption of transcriptional termination can be observed in RNA-seq data in which sequencing reads map tens of kilobases past the 3' ends of thousands of mRNA genes and into downstream intergenic regions. We are interested in discovering what allows Pol II to proceed past the normal termination point when cells respond to heat shock. We have shown by Pol II ChIP-seq that after heat shock the polymerase no longer pauses near the 3' ends of mRNA genes, a normal mechanistic step in termination, rather the polymerase continues to occupy the genome kilobases beyond the 3' ends. These lines of research address new and fundamental questions about the relationship between cellular adaptation to stress and control of Pol II transcription.