Dr Keith Brown

Reader in Molecular Pathology

School of Cellular and Molecular Medicine,
University of Bristol, Medical Sciences Building,
Bristol, BS8 1TD

phone: +44 (0)117 33 12071 (internal 12071)
email: keith.brown@bristol.ac.uk

group: Cancer Epigenetics Lab

Research interests

My research interests are in the molecular genetics of cancer, concentrating in particular on epigenetic changes in childhood cancers and in cancer stem cells.

Epigenetic alterations are heritable modifications of DNA that do not affect the primary sequence, such as methylation of cytosines in CpG dinucleotides. DNA methylation at CpG residues affects gene expression by directly inhibiting transcription factor access to DNA or indirectly by attracting methyl-binding proteins that associate with modifiers of chromatin structure, such as histone deacetylases. Cancers usually have an overall hypomethylation of the genome, probably leading to chromosomal instability, accompanied by gene-specific hypermethylation that inactivates tumour suppressor genes.

Epigenetics of childhood cancers

Current projects are characterizing genome-wide DNA methylation changes in clinically important childhood cancers, such as Wilms' tumour of the kidney and neuroblastoma, a cancer of the sympathetic nervous system, and understanding the functional consequences of these changes. This is being achieved by the use of human promoter microarrays, hybridized with tumour DNA enriched for methylated sequences. This technique gives genome-wide coverage of methylation changes in cancer, thus identifying new prognostic markers and targets for therapy. This will identify genes that are abnormally methylated in childhood cancers, which will then be further studied using functional analyses in cultured cells.

The results of this work are designed to give the following outcomes that could impact on the clinical management of childhood cancers:

  1. Identification of new prognostic markers.
  2. Identification of genes that represent new targets for therapy.
  3. Determine whether the pattern of overall genome methylation in would allow therapy based on targeting the mechanisms that regulate DNA methylation.

Epigenetic regulation of cancer stem cells

A small subpopulation of tumour initiating cells is thought to underlie the persistent growth of cancers and these are often referred to as "cancer stem cells". Cancer stem cells may represent transformed normal stem cells, although other populations could acquire stem cell-like properties and "stemness" can be regulated by external factors, including the tumour microenvironment and treatment.

Current work aims to determine how stem cell markers are regulated in normal tissues and during tumorigenesis, with special reference to epigenetic modifications that play a pivotal role in modulating stemness.  This work is using colorectal cancer cell lines to study epigenetic marks (DNA methylation and histone modifications) that may regulate stem cell markers in normal intestinal tissue and malignant cells, and how dietary factors and the tumour microenvironment regulate them.

Selected publications

View all publications for Dr Brown on his Bristol Research Profile page