SWI/SNF chromatin remodelling in the regulation of cell cycle, growth, and development
Supervisor:Dr. Nick Burton
Second Supervisor: Dr. Eric Miska
Second Supervisors DepartmentGurdon Institute
The 15 subunits of the SWI/SNF chromatin remodelling complex are mutated in >20% of all human cancers1, making SWI/SNF one of the most frequently mutated complexes in cancer. However, the precise mechanisms by which mutations in SWI/SNF promote oncogenesis are complex, and both loss-of-function and gain-of-function mutations have been found to contribute to oncogenesis1. For example, 100% of cases of synovial sarcoma are caused by a gain-of-function mutation in the SWI/SNF subunit SS18, while nearly 100% of rhabdoid tumors are caused by loss-of-function mutations in the SWI/SNF subunit BAF471.
To further understand how SWI/SNF activity regulates the cell cycle, growth, and development we have begun work on a model of SWI/SNF function in the nematode C. elegans. Loss-of-function mutations in the SWI/SNF subunit SWSN-1 result in animals that arrest development immediately after hatching, which includes arresting cell division and cell growth2. We screened for mutations that restore growth and development in swsn-1 mutant animals and identified several such mutations. We propose that the identification of these mutations will enhance our understanding of how SWI/SNF activity promotes the cell cycle and cell growth and could lead to the identification of novel therapeutic targets for cancers driven by abnormal SWI/SNF activity.
The successful candidate will use a variety of genetic and biochemical techniques to identify these mutations and determine how SWI/SNF activity regulates growth and development in C. elegans. In addition, the candidate will use RNA-seq to study the effects of these mutations on gene expression.
For further information please contact Dr. Nick Burton. email: email@example.com
This project includes investigating whether specific small molecule inhibitors might be used as potential therapeutics for cancers resulting from the loss of SWI/SNF activity.