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Understanding the role of nuclear myosin in the spatial organisation of transcription

Reference	BB/X008460/1
Principal Investigator / Supervisor	Dr Christopher Toseland
Co-Investigators / Co-Supervisors
Institution	University of Sheffield
Department	Oncology and Metabolism
Funding type	Research
Value (£)	502,412
Status	Current
Type	Research Grant
Start date	01/04/2023
End date	31/03/2026
Duration	36 months

Abstract

In eukaryotic cells, RNA polymerase II (RNAPII) directs the flow of genetic information from DNA to mRNA. Detailed genetic and biochemical assays have revealed a multi-level regulation of transcription, including the general transcription factors, activators and repressors. This occurs both distal and proximal to the gene through physical interactions. While it is widely accepted there is temporal regulation of gene expression, more recently there has been an increase in reports proposed spatial regulation. The spatial organization of transcription has been debated and studied for over three decades. My research has identified the actin-based molecular motor, myosin VI, as a critical regulator of spatial organisation with respect to transcription initiation. We found that myosin VI has the ability to hold RNAPII at transcription sites. The loss of inhibition of myosin VI ATPase activity leads to disruption of RNAPII organisation and a reduction in gene expression. With this project, we now wish to understand how myosin VI is regulated within the nucleus to understand the molecular mechanism underpinning its role in transcription. Moreover, we also wish to explore how myosin's role extends throughout the transcription cycle, along with the relationship to other myosins involved in transcription. We will perform this work using state-of-the-art single molecule imaging techniques (SMLM) and in vitro single molecule experiments. This interdisciplinary approach will allow us to directly address how regulation of myosin VI related to gene expression and how it interacts with other nuclear myosin proteins. These findings will be fundamental for understanding the spatial organisation of transcription and how perturbation may occur during disease and aging. This may also reveal routes for developing therapeutic strategies.

Summary

The regulation of gene expression is essential for healthy living. Gene expression is one of the most fundamental processes in biology. In eukaryotic cells, RNA polymerase II (RNAPII) directs the flow of genetic information from DNA to mRNA. Detailed genetic and biochemical assays have revealed a multi-level regulation of transcription, including the general transcription factors, activators and repressors. This occurs both distal and proximal to the gene through physical interactions. A cell's response to stimulus requires coordinated and efficient regulation of many genes. While it is widely accepted there is temporal regulation of gene expression, more recently there has been an increase in reports proposed spatial regulation. The spatial organization of transcription has been debated and studied for over three decades. The formation of RNAPII clusters enables distal genomic contacts while increasing the local concentration of enzymes, which enhances efficiency. We have identified the actin-based molecular motor, myosin VI, as a critical regulator of this spatial organisation with respect to transcription initiation. Our previous work has revealed that myosin VI directly binds RNAPII and it can bind DNA. Our current work has revealed that myosin VI has the ability to aid the organisation of transcription initiation by holding RNAPII at transcription sites. The loss of inhibition of myosin VI ATPase activity leads to disruption of RNAPII organisation and a reduction in gene expression. We now wish to understand how myosin VI is regulated in this role and how widespread this effect is throughout the transcription cycle (e.g. during elongation). These findings will be fundamental for understanding the spatial organisation of transcription and how perturbation may occur during disease and aging. This may also reveal routes for developing therapeutic strategies. We will perform this work using state-of-the-art single molecule imaging techniques. This interdisciplinary approach will allow us to directly address how regulation of myosin VI related to gene expression.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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