CBX7 and other Polycomb genes in health and disease
Lead Research Organisation:
Queen Mary University of London
Department Name: UNLISTED
Abstract
The expected outcomes of this research are the following. A greater understanding of the mechanisms by which a key oncogenic locus is regulated. Elaboration of the role of newly identified genes in animal and human cancer. If appropriate these studies will be moved towards greater clinical application.
Technical Summary
We have identified the CBX7 gene as a critical global regulator of the INK4A locus that itself encodes two tumour suppressor proteins that regulate p53 and rb. Mutation or modification of the INK locus has been found to be the second most frequent perturbation in cancer. Thus, there is great interest in genes such as CBX7 that regulate the INK locus.
CBX7 is a member of the large polycomb group of proteins, originally identified in Drosophila. They are thought to act, at least in part, through histone modification in target loci and thus can set up epigenetic chromatin modifications that are heritable through cell division and animal development. Our initial observations suggest that CBX7 is itself an oncogene, that associates with a newly identified histone methyl transferase.
In this proposal we have five specific objectives. The role of CBX7 in oncogenic transformation. This will extend our initial observation that CBX7 can act as an oncogene in the mouse immune system, in continuing mouse work but also by analysis of human tumours. Mechanisms of transcriptional regulation by CBX7. Chromatin immunoprecipitation studies indicate that CBX7 acts through histone methylation at the INK locus. We will define the relevant target DNA elements required, identify further proteins that function with CBX7 (see below) and evaluate their biological roles. Analysis of CBX7 function in vivo. The closest functional relative of CBX7 is the Bmi1 polycomb protein, that also acts at the INK locus. Loss-of-function Bmi causes, inter alia, defects in stem cell renewal. Thus we will do a variety of CBX7 mouse knock-out studies and with appropriate genetic crosses elaborate the role of this gene in normal development and in adult life. Comparative dissection of the composition of Pc containing complexes. A variety of approaches will be taken to identify proteins, other than those we have already identified, that act in concert with CBX7 in gene regulation. Role of other PcG in oncogenesis. In silico and other approaches have led us to five polycomb group proteins that are likely oncogenes, in common with CBX7 and Bmi1. These will be explored, genetically and biochemically.
CBX7 is a member of the large polycomb group of proteins, originally identified in Drosophila. They are thought to act, at least in part, through histone modification in target loci and thus can set up epigenetic chromatin modifications that are heritable through cell division and animal development. Our initial observations suggest that CBX7 is itself an oncogene, that associates with a newly identified histone methyl transferase.
In this proposal we have five specific objectives. The role of CBX7 in oncogenic transformation. This will extend our initial observation that CBX7 can act as an oncogene in the mouse immune system, in continuing mouse work but also by analysis of human tumours. Mechanisms of transcriptional regulation by CBX7. Chromatin immunoprecipitation studies indicate that CBX7 acts through histone methylation at the INK locus. We will define the relevant target DNA elements required, identify further proteins that function with CBX7 (see below) and evaluate their biological roles. Analysis of CBX7 function in vivo. The closest functional relative of CBX7 is the Bmi1 polycomb protein, that also acts at the INK locus. Loss-of-function Bmi causes, inter alia, defects in stem cell renewal. Thus we will do a variety of CBX7 mouse knock-out studies and with appropriate genetic crosses elaborate the role of this gene in normal development and in adult life. Comparative dissection of the composition of Pc containing complexes. A variety of approaches will be taken to identify proteins, other than those we have already identified, that act in concert with CBX7 in gene regulation. Role of other PcG in oncogenesis. In silico and other approaches have led us to five polycomb group proteins that are likely oncogenes, in common with CBX7 and Bmi1. These will be explored, genetically and biochemically.
People |
ORCID iD |
| David Beach (Principal Investigator) |