Graham Brock, Ph.D.

Staff Scientist, Cancer Center, Ordway Research Institute
Director, Target and Drug Discovery Facility, Ordway Research Institute

Target and Drug Discovery Facility

The MicrobrewRNA

Telephone: (518) 641-6487
Fax: (518) 641-6305
gbrock@ordwayresearch.org

Research Focus

During tumor progression ordinarily unmethylated cytosines in promoter regions (known as CpG islands due to the relative frequency of the dinucleotide CpG) become methylated. Additional modification to the core histones also occurs at the nuclesome level and alters the chromatin status. It is thought that these two processes are linked through protein complexes, which bind both methylated cytosines and the altered chromatin. While the chronology of events is still disputed, in promoter regions, methylation of cytosine and deacetylation of histone indicates heterochromatin and stable repression of the associated gene.

Dr Brock's research has focused on the identification of methylation changes during the progression of breast cancer. However, multiple tumour types share many CpG Island targets, perhaps indicating common pathways in other cancers. The identification of altered promoters will lead to a better understanding of the mechanisms involved and will also provide useful biomarkers for tumor progression and response to therapy. Investigation has focused on a collection of CpG Islands identified as methylated in breast cancer tumors but not in normal tissue (recently generated using a novel technique). The function of these repressed genes their associated pathways and the frequency and timing of the repression are being examined.

Finally in contrast to point mutations and deletions, these epigenetic modifications are reversible and both the inhibition of histone deaceytylases and disruption to the methylation machinery can result in the restoration of expression. By linking the capabilities of the Target and Drug Discovery Facility (TDDF) and previous investigation into patterns of methylation we also hope to identify novel inhibitors of methylation and chromatin modification.

Selected Publications

Chen, C. M., Chen, H. L., Hsiau, T. H., Hsiau, A. H., Shi, H., Brock, G. J., Wei, S. H., Caldwell, C. W., Yan, P. S., and Huang, T. H. Methylation target array for rapid analysis of CpG island hypermethylation in multiple tissue genomes. Am J Pathol, 163: 37-45, 2003.

Brock, G. J., Huang, T. H., Chen, C. M., and Johnson, K. J. A novel technique for the identification of CpG islands exhibiting altered methylation patterns (ICEAMP). Nucleic Acids Res, 29: E123, 2001.

Brock, G. J., Anderson, N. H., and Monckton, D. G. Cis-acting modifiers of expanded CAG/CTG triplet repeat expandability: associations with flanking GC content and proximity to CpG islands. Hum Mol Genet, 8: 1061-1067, 1999.

Brock, G. J., Charlton, J., and Bird, A. P. Densely methylated sequences that are preferentially localized at telomere-proximal regions of human chromosomes. Gene, 240: 269-277, 1999.

Brock, G. J. and Bird, A. Mosaic methylation of the repeat unit of the human ribosomal RNA genes. Hum Mol Genet, 6: 451-456, 1997.

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