Epigenetic Deregulation in Cancer Group

Our research has focused on mapping epigenetic alterations in cancer, with a focus on breast and prostate cancer. The group has made significant contributions to the discovery of Long Range Epigenetic deregulation in cancer, which includes both regional gene silencing and gene activation. A keen interest 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 revealed the intimate relationship between gene expression, DNA hypermethylation and chromatin modifications. We have also had a research interest to understand the role of the epigenetic modifier MBD2 in the spread of DNA methylation and its role in aberrant DNA methylation in cancer. More recently, the group has shown a key role for histone lysine 4 mono-methylation chromatin mark in demarcating regions that become hypermethylated 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. The group are now actively pursuing the discovery and development of DNA methylated biomarkers, through whole-genome methylation profiling of normal and tumour DNA in breast cancer, with a focus on predictive and prognostic biomarkers for stratification of Triple Negative Breast Cancers, as well as a Pan-breast cancer methylated biomarker panel for monitoring circulating tumour DNA in order to detect disease relapse and minimal residual disease.

Selected Publications

2021

Du Q, Smith GC, Luu PL, Ferguson JM, Armstrong NJ, Caldon CE, Campbell E, Nair SS, Zotenko E, Gould CM, Buckley M, Kaczorowski D, Barton K, Deveson IW, Smith MA, Powell JE, Skvortsova K, Stirzaker C, Achinger-Kawecka J, Clark SJ. (2021). DNA methylation is required to maintain both DNA replication timing precision and 3D genome organisation integrity. Cell Reports 36:109722.

Phuc LL, Phuc TO, Tran THL, Lam D, Pidsley R, Stirzaker C, Clark SJ. (2021) MethPanel: a parallel pipeline and interactive analysis tool for multiplex bisulphite PCR sequencing to assess DNA methylation biomarker panels for disease detection. Bioinformatics. 37(15):2198–2200. PMID: 33367555

Cole AJ, Dickson KA, Liddle C, Stirzaker C, Shah JS, Clifton-Bligh R, Marsh DJ. (2021). Ubiquitin chromatin remodelling after DNA damage is associated with the expression of key cancer genes and pathways.Cell Mol Life Sci. 78(3):1011-1027. PMID: 32458023

Kristina Warton,Clare Stirzaker, Goli Samimi, Susan Clark. 2021. Chapter: “Methylation analysis of circulating DNA”. “Circulating Cell-Free DNA – Purification and Analysis Techniques”, Edited by Dr Kristina Warton and Dr Goli Samimi; World Scientific Publishing 2021.

2020

Joanna Achinger-Kawecka, Fatima Valdes-Mora, Phuc Luu, Katherine Giles, C Caldon, Wenjia Qu, Shalima Nair, Sebastian Soto, Warwick Locke, Nicole Yeo-Teh, Cathryn Gould, Qian Du, Grady Smith, Irene Ramos, Kristine Fernandez, Dave Hoon, Julia Gee, Clare Stirzaker, and Susan Clark (2020). Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine resistant breast cancer. Nature Communications 11 (1), 320 2020 PMID: 31949157 PMCID: PMC6965612 DOI: 10.1038/s41467-019-14098-x

Amanda Khoury, Joanna Achinger-Kawecka, Saul Bert, Grady Smith, Hugh French, Phuc Luu, Timothy Peters, Qian Du, Aled Parry, Fatima Valdes-Mora, Phillippa Taberlay, Clare Stirzaker, Aaron Statham, and Susan Clark (2020) Constitutively bound CTCF sites maintain 3D chromatin architecture and long-range epigenetically regulated domains. Nature Communications 2020 11 (1), 1-13 PMID: 31911579 PMCID: PMC6946690 DOI: 10.1038/s41467-019-13753-7

2019

Ksenia Skvortsova, Etienne Masle-Farquhar, Phuc-Loi Luu, Jenny Z. Song, Wenjia Qu, Elena Zotenko, Cathryn M. Gould, Qian Du, Timothy Peters,Yolanda Colino-Sanguino, Ruth Pidsley, Shalima, S. Nair, Amanda Khoury¹, Grady C. Smith, Lisa A. Miosge, Joanne H. Reed, James G. Kench, Mark A. Rubin, Lisa Horvath, Ozren Bogdanovic, Sue Mei Lim, Jose M. Polo, Christopher C. Goodnow, Clare Stirzaker* & Susan J. Clark* (2019) DNA hypermethylation encroachment at CpG island borders in cancer is predisposed by H3K4 mono-methylation patterns. * equal senior Cancer Cell 35 (2), 297-314.e8 ; Feb 112019 PMID: 30753827 DOI: 10.1016/j.ccell.2019.01.004

Du Q, Bert SA, Armstrong NJ, Caldon CE, Song JZ, Nair SS, Gould CM, Luu PL, Peters T, Khoury A, Qu W, Zotenko E, Stirzaker C, Clark SJ. (2019) Replication timing and epigenome remodelling are associated with the nature of chromosomal rearrangements in cancer. Nat Commun. Jan 2019 PMID: 30679435 PMCID: PMC6345877 DOI: 10.1038/s41467-019-08302-1

Giles KA, Gould CM, Du Q, Skvortsova K, Song JZ, Maddugoda MP, Achinger-Kawecka J, Stirzaker C, Clark SJ, Taberlay PC.(2019) Integrated epigenomic analysis stratifies chromatin remodellers into distinct functional groups. Epigenetics Chromatin. Feb 12 (1), 12 2019 PMID: 30755246 PMCID: PMC6371444 DOI: 10.1186/s13072-019-0258-9

Bradford ST, Nair SS, Statham AL, van Dijk SJ, Peters TJ, Anwar F, French HJ, von Martels JZH, Sutcliffe B, Maddugoda MP, Peranec M, Varinli H, Arnoldy R, Buckley M, Ross JP, Zotenko E, Song JZ, Stirzaker C, Bauer DC, Qu W, Swarbrick MM, Lutgers HL, Lord RV, Samaras K, Molloy PL, Clark SJ (2019). Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal key epigenetic differences at developmental genes. Scientific Reports. Jul 2019 PMID: 31266983 PMCID: PMC6606599 DOI: 10.1038/s41598-019-45777-w

Peters TJ, French HJ, Bradford ST, Pidsley R, Stirzaker C, Varinli H, Nair S, Qu W, Song J, Giles KA, Statham AL, Speirs H, Speed TP, Clark SJ. (2019) Evaluation of cross-platform and interlaboratory concordance via consensus modelling of genomic measurements. Bioinformatics. 2019 Feb 15;35(4):560-570. doi: 10.1093/bioinformatics/bty675.

R Pidsley, C Stirzaker (2019). Cancer Methylation Biomarkers in Circulating Cell-Free DNA. Clinical Epigenetics, 217-245. Publisher Springer, Singapore. Editors: Luke Hesson and Antonia Pritchard (review)

K Skvortsova, C Stirzaker, P Taberlay (2019) The DNA methylation landscape in cancer. Essays in Biochemistry 63 (6), 797-811 (review) PMID: 31845735 PMCID: PMC6923322 DOI: 10.1042/EBC20190037

2018

Peters TJ, French HJ, Bradford ST, Pidsley R, Stirzaker C, Varinli H, Nair S, Qu W, Song J, Giles KA, Statham AL, Speirs H, Speed TP, Clark SJ. (2018) Evaluation of cross-platform and interlaboratory concordance via consensus modelling of genomic measurements. Bioinformatics. 35 (4), 560-570 2019 Feb 152018 . PMID: 30084929 PMCID: PMC6378945 DOI: 10.1093/bioinformatics/bty675

Ruth Pidsley, Mitchell G Lawrence, Elena Zotenko, Birunthi Niranjan, Aaron Statham, Jenny Song, Roman M Chabanon, Wenjia Qu, Hong Wang, Michelle Richards, Shalima S Nair, Nicola J Armstrong, Hieu T Nim, Melissa Papargiris, Preetika Balanathan, Hugh French, Timothy Peters, Sam Norden, Andrew Ryan, John Pedersen, James Kench, Roger J Daly, Lisa G Horvath, Phillip Stricker, Mark Frydenberg, Renea A Taylor, Clare Stirzaker, Gail P Risbridger, Susan J Clark (2018) Enduring Epigenetic marks define the cancer microenvironment. Genome Research. April. PMID: 29650553 PMCID: PMC5932604 DOI: 10.1101/gr.229070.117

2017

Valdés-Mora F, Gould CM, Colino-Sanguino Y, Qu W, Song JZ, Taylor KM, Buske FA, Statham AL, Nair SS, Armstrong NJ, Kench JG, Lee KML, Horvath LG, Qiu M, Ilinykh A, Yeo-Teh NS, Gallego-Ortega D, Stirzaker C, Clark SJ (2017). Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer. Nature Communications 8:1346. doi: 10.1038/s41467-017-01393-8.

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. Clark^1,2Methyl-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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