Investigating the role of Chromatin in coupling RNA quality control to transcription

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Quality control of the 'RNA life-cycle' is crucial for cellular homeostasis. To avoid abnormal mRNA synthesis, typically RNA polymerase II (RNA Pol II) will prematurely abort transcription, leading to the degradation of the nascent RNA transcript within the nucleus.The pathway characterising the degradation of RNA is known in molecular detail, however the mechanisms which regulate the termination of transcription are unclear. Additionally, it is also unclear whether these mechanisms are conserved throughout eukaryotes. Transcription within eukaryotes occurs within the connect of the condensed, dynamic nucleoprotein chromatin structure. RNA Pol II is known to pause frequently during transcription, and within S. cerevisiae, this pausing at specific DNA sequences is associated with the loading of both RNA surveillance factors and transcription termination factors onto the mRNA transcript. INO80, an ATP-dependant chromatin remodeller which controls incorporation of the histone variant H2A.Z, has been found to promote premature termination and is able to counteract the accumulation of RNA Pol II pausing sites. Deletion of H2A.Z has shown to lead to defects in premature termination of transcription.Furthermore, following truncation of the heavily post-translationally modified N-terminal tail of the histone H3, increased early termination is observed, indicating an important role in controlling premature termination of transcription. This project will investigate how Chromatin dictates whether RNA Pol II progresses into productive elongation, or is removed leading to premature termination. Specifically, the histone variant H2A.Z's role in this process will be explored, along with the use of human-gene orthologues and cancer-cell lines to identify conserved mechanisms of termination control.