Epigenetic gene regulation is important in normal cell growth and differentiation and is commonly deregulated in many diseases, including cancer. Epigenetic regulation includes DNA methylation, post-translational histone modification, exchange of histone variants and alterations in nucleosome positioning. Implementation of genome-wide technologies has allowed very precise epigenome maps of epigenetic alterations to be defined in cancer. The distribution of histone variants however and any potential role of post-translational modification of histone variants in gene regulation has not been fully characterized.
The research interests of the Histone Variants Group is to fully understand the molecular mechanisms of how histone variants, in particular the histone variant H2A.Z, regulate aberrant gene transcription in cancer. We are working on two different types of cancer: prostate cancer and anti-estrogen resistant breast cancer.
We recently discovered that acetylation of the histone variant H2A.Z (H2A.Zac) is associated with oncogene activation in cancer. Our exciting finding adds an entirely new dimension to the “histone code”, because for the first time we have shown that the post-translation modification of a histone variant can be deregulated in cancer, correlating with aberrant gene expression. There are however still many unresolved key questions concerning the mechanism by which H2A.Z acetylation promotes gene activation.
In the prostate cancer project we are performing genome-wide analyses to study the effects of H2A.Z and/or H2A.Zac in gene deregulation and how this histone variant interacts with other epigenetic mechanisms with a particular focus on nucleosome positioning.
In the anti-estrogen resistant breast cancer project we are interested on understanding the epigenetic reprogramming of the transcription factor Elf5. Elf5 is a novel key determinant in endocrine therapy resistance. Understanding the molecular mechanisms of resistance would benefit a large number of women with hormone-resistant breast cancer. We are currently studying the involvement of epigenetic factors, including histone variants, on the regulation of the expression of Elf5 during the acquisition of anti-estrogen resistance.
Valdés-Mora F#, Gould CM, Qu W, Buske FA, Statham AL, Nair SS, Armstrong NJ, Kench JG Lee KML, Horvath LG, Qiu M, Colino-Sanguino Y, Gallego-Ortega D, Song JZ, Stirzaker C and Clark SJ#. Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer. Nat Commun. 2017 Nov 7;8(1):1346. (#Co-corresponding authors).
Colino-Sanguino Y, Clark SJ, Valdes-Mora F. H2A.Z acetylation and transcription: ready, steady, go! Epigenomics. 2016 Apr 18. [Epub ahead of print]
Valdes-Mora F & Clark SJ. Prostate Cancer Epigenetic Biomarkers: next generation technologies. Oncogene. 2014 May 19;0. doi: 10.1038/onc.2014.111.2014
Stone A, Cowley MJ, Valdes-Mora F, McCloy RA, Sergio CM, Gallego-Ortega D, Caldon CE, Ormandy CJ, Biankin AV, Gee JM, Nicholson RI, Print CG, Clark SJ, Musgrove EA. BCL-2 hypermethylation is a potential biomarker of sensitivity to antimitotic chemotherapy in endocrine-resistant breast cancer. Mol Cancer Ther. 2013; 12(9):1874-85.
Kalyuga M, Gallego-Ortega D, Lee HJ, Roden DL, Cowley MJ, Caldon CE, Stone A, Allerdice SL, Valdes-Mora F, Launchbury R, Statham AL, Armstrong N, Alles MC, Young A, Egger A, Au W, Piggin CL, Evans CJ, Ledger A, Brummer T, Oakes SR, Kaplan W, Gee JM, Nicholson RI, Sutherland RL, Swarbrick A, Naylor MJ, Clark SJ, Carroll JS, Ormandy CJ. ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer. PLoS Biol. 2012; 10(12):e1001461.
Stone A, Valdés-Mora F, Gee JM, Farrow L, McClelland RA, Fiegl H, Dutkowski C, McCloy RA, Sutherland RL, Musgrove EA, Nicholson RI. Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer. PLoS One. 2012; 7(7):e40466.
Lee HJ, Hinshelwood RA, Bouras T, Gallego-Ortega D, Valdés-Mora F, Blazek K, Visvader JE, Clark SJ, Ormandy CJ. Lineage specific methylation of the Elf5 promoter in mammary epithelial cells. Stem Cells. 2011; 29(10):1611-9.
Valdés-Mora F, Song JZ, Statham AL, Strbenac D, Robinson MD, Nair SS, Patterson KI, Tremethick DJ, Stirzaker C, Clark SJ. Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer. Genome Res. 2012; 22(2):307-21.
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