EPIGENETIC DEREGULATION IN CANCER
Our research interest has focused on mapping epigenetic deregulation in cancer, focusing on prostate cancer. We have made significant contributions to the discovery of Long Range Epigenetic deregulation in cancer, including regional gene silencing and activation. A focus of the group has been to understand the mechanism underlying aberrant DNA methylation.
Early work on the GSTP1 gene in prostate cancer elucidated the ‘trigger’ of aberrant DNA methylation in prostate cancer cells and we went on to elucidate the intimate relationship between gene expression, DNA hypermethylation and chromatin modifications in prostate cancer cells. Our current research interest is to understand the role of the epigenetic modifier MBD2 in the spread of DNA methylation and its role in aberrant DNA methylation in cancer.
The group has also played an integral role in developing new epigenetic technologies, including ongoing optimization of bisulphite sequencing for DNA methylation analysis which is the “gold standard” method for DNA methylation analysis, chromatin immunoprecipitation, RNA-seq, and the development of genome-wide analysis of methylated DNA and chromatin modifications by next-generation sequencing. Recently the ChIP-bis approach was developed enabling the direct interrogation of chromatin modifications and DNA methylation.
Skvortsova K, Zotenko E, Luu PL, Gould CM, Nair SS, Clark SJ, Stirzaker C. Comprehensive evaluation of genome-wide 5-hydroxymethylcytosine profiling approaches in human DNA. Epigenetics Chromatin. 2017 Apr 20;10:16. PMID: 28428825
Clare Stirzaker1,2, Jenny Z. Song1, Wendy Ng1, Qian Du1, Nicola Armstrong3, Warwick Locke1, Aaron Statham1, Hugh French1, Ruth Pidsley1, Fatima Valdes-Mora1, Elena Zotenko1 & Susan J. Clark1,2 Methyl-CpG-Binding Protein MBD2 plays a key role in maintenance and spread of DNA methylation at CpG islands and shores in cancer. Oncogene. 2017 Mar;36(10):1328-1338. PMID:27593931
Pidsley R, Zotenko E, Peters TJ, Lawrence MG, Risbridger GP, Molloy P, Van Djik S, Muhlhausler B, Stirzaker C*, Clark SJ*. Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling .*equal senior authors Genome Biol. 2016 Oct 7;17(1):208 PMID:27717381
Clare Stirzaker*, Phillippa C.Taberlay*, Aaron L. Statham, Susan J. Clark Mining Cancer Methylomes: prospects and challenges Trends in Genetics. 2014 Feb;30(2):75-84.. *authors contributed equally to the work PMID: 24368016
Stirzaker C*, Zotenko E*, Song JZ, Qu W, Nair SS, Locke WJ, Stone A, Armstong NJ, Robinson MD, Dobrovic A, Avery-Kiejda KA, Peters KM, French JD, Stein S, Korbie DJ, Trau M, Forbes JF, Scott RJ, Brown MA, Francis GD, Clark SJ. Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value. Nature Communications. 2015; Feb 2;6: 5899 Equal *first authors
Saul A Bert, Mark D Robinson, Dario Strbenac, Aaron L Statham, Jenny Z Song, Toby Hulf, Robert L Sutherland, Marcel W Coolen, Clare Stirzaker & Susan J Clark. Regional Activation of the Cancer Genome by Long Range Epigenetic Remodelling Cancer Cell 2013; 23: 9-22,
Aaron L. Statham,*, Mark D. Robinson*, Jenny Z. Song, Marcel W. Coolen, Clare Stirzaker# and Susan J. Clark#. Bisulphite-sequencing of chromatin immunoprecipitated DNA (BisChIP-seq) directly informs methylation status of histone-modified DNA. Genome Research. March 2012 Equal *first authors and #last authors
Marcel W. Coolen*, Clare Stirzaker*, Jenny Z. Song, Aaron L. Statham, Zena Kassir, Carlos S. Moreno, Andrew N. Young, Vijay Varma, Terence P. Speed, Mark Cowley, Paul Lacaze, Warren Kaplan, Mark D. Robinson, and Susan J. Clark. Consolidation of the cancer genome into domains of repressive chromatin by long range epigenetic silencing (LRES) reduces transcriptional plasticity. Nature Cell Biology 2010; 12(3): 235-46. *authors contributed equally to the work,
Frigola J, Song J, Stirzaker C, Hinshelwood RA, Peinado MA, Clark SJ. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nat Genet. 2006; 38(5):540-9.
Clark SJ, Statham A, Stirzaker C, Molloy PL, Frommer M. DNA methylation: bisulphite modification and analysis. Nat Protoc. 2006; 1(5):2353-64.
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Senior Research Assistant