4 South 0.56
Tel: +44 (0) 1225 38 3583
Dr Adele Murrell
Higher-order-chromatin-structure and epigenetic modifications to DNA and histones shape the genome within the nucleus. We are investigating how tumorigenesis and metastasis disrupt genome organisation and how this leads to the aberrant expression of several genes related to cancer cell survival.
Genomic Imprinting as a Model Epigenetic System
The phenomenon of genomic imprinting is an ideal model-system for functional epigenetic analysis. Imprinted genes are a network of epigenetically regulated genes involved in foetal growth. They are expressed from one allele in a parent-of-origin specific manner and are controlled by cooperating epigenetic mechanisms that are widely applicable to the understanding of genome organisation and gene expression in general. In addition to DNA methylation changes, these mechanisms include transcriptional interference and/ or recruitment of chromatin modifiers by noncoding RNAs and partitioning the genome into looping domain structures bordered by CTCF and cohesin.
Long Range Epigenetic Silencing in Cancer
In cancer several contiguous genes along a chromosome region can be simultaneously silenced. This is known as long range epigenetic silencing (LRES). Our goal is to understand how LRES originates and spreads. It is likely that this process employs similar mechanisms to genomic imprinting. We are studying an LRES region that contains the imprinted tumour suppressor gene DIRAS3 and an associated long non coding RNA, both of which are silenced in multiple cancers including breast and prostate cancer.
Epigenetic Reprogramming during metastasis
When cells metastasise from a primary cancer site to a new site, they undergo epigenetic reprogramming events that enable them to migrate, infiltrate, adapt and colonise a new environment. Our future goal is to identify the triggers of these epigenetic changes with a view to prevent metastasis. At present we are looking at colon cancer and liver metastasis and focusing on changes in DNA methylation and its demethylation intermediates such as 5-hydroxymethylcytosine.
Ross-Adams, H., Ball, S., Lawrenson, K., Halim, S., Russell, R., Wells, C., Strand, S. H., Ørntoft, T. F., Larson, M., Armasu, S., Massie, C. E., Asim, M., Mortensen, M. M., Borre, M., Woodfine, K., Warren, A. Y., Lamb, A. D., Kay, J., Whitaker, H., Ramos-Montoya, A., Murrell, A., Sørensen, K. D., Fridley, B. L., Goode, E. L., Gayther, S. A., Masters, J., Neal, D. E. and Mills, I. G., 2016. HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. Oncotarget, 7 (46), pp. 74734-74746.
Murrell, A., 2016. What lies beneath the epigenetic signatures associated with breast cancer and how do we find out? In: UK Breast Cancer Research Symposium, 2016-07-22 - 2016-07-23, London.
Stojic, L., Niemczyk, M., Orjalo, A., Ito, Y., Ruijter, A. E. M., Uribe-Lewis, S., Joseph, N., Weston, S., Menon, S., Odom, D. T., Rinn, J., Gergely, F. and Murrell, A., 2016. Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions:2. Nature Communications, 7, 10406.
Bachman, M., Uribe-Lewis, S., Yang, X., Burgess, H. E., Iurlaro, M., Reik, W., Murrell, A. and Balasubramanian, S., 2015. 5-Formylcytosine can be a stable DNA modification in mammals. Nature Chemical Biology, 11 (8), pp. 555-557.
Uribe-lewis, S., Stark, R., Carroll, T., Dunning, M. J., Bachman, M., Ito, Y., Stojic, L., Halim, S., Vowler, S. L., Lynch, A. G., Delatte, B., De Bony, E. J., Colin, L., Defrance, M., Krueger, F., Silva, A.-l., Ten Hoopen, R., Ibrahim, A. E., Fuks, F. and Murrell, A., 2015. 5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. Genome Biology, 16 (1), 69.
Huntriss, J., Woodfine, K., Huddleston, J. E., Murrell, A. and Picton, H. M., 2015. Analysis of DNA methylation patterns in single blastocysts by Pyrosequencing(®). In: Lehmann, U. and Tost, J., eds. Pyrosequencing. New York, U. S. A.: Springer, pp. 259-270.
Bachman, M., Uribe-Lewis, S., Yang, X., Williams, M., Murrell, A. and Balasubramanian, S., 2014. 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nature Chemistry, 6, pp. 1049-1055.
Murrell, A., 2014. Cross-talk between imprinted loci in Prader-Willi syndrome. Nature Genetics, 46 (6), pp. 528-530.
Wu, L., Murat, P., Matak-Vinkovic, D., Murrell, A. and Balasubramanian, S., 2013. Binding interactions between long noncoding RNA HOTAIR and PRC2 proteins. Biochemistry, 52 (52).
Niemczyk, M., Ito, Y., Huddleston, J., Git, A., Abu-Amero, S., Caldas, C., Moore, G. E., Stojic, L. and Murrell, A., 2013. Imprinted chromatin around DIRAS3 regulates alternative splicing of GNG12-AS1, a long noncoding RNA. American Journal of Human Genetics, 93 (2), pp. 224-235.
Méndez-Catalá, C. F., Gretton, S., Vostrov, A., Pugacheva, E., Farrar, D., Ito, Y., Docquier, F., Kita, G.-X., Murrell, A., Lobanenkov, V. and Klenova, E., 2013. A novel mechanism for CTCF in the epigenetic regulation of Bax in breast cancer cells. Neoplasia : An International Journal for Oncology Research, 15 (8), pp. 898-912.
Ito, Y., Nativio, R. and Murrell, A., 2013. Induced DNA demethylation can reshape chromatin topology at the IGF2-H19 locus. Nucleic Acids Research, 41 (10), pp. 5290-302.
Mulder, K. W., Wang, X., Escriu, C., Ito, Y., Schwarz, R. F., Gillis, J., Sirokmány, G., Donati, G., Uribe-Lewis, S., Pavlidis, P., Murrell, A., Markowetz, F. and Watt, F. M., 2012. Diverse epigenetic strategies interact to control epidermal differentiation. Nature cell biology, 14 (7), pp. 753-63.
Sun, B., Ito, M., Mendjan, S., Ito, Y., Brons, I. G. M., Murrell, A., Vallier, L., Ferguson-Smith, A. C. and Pedersen, R. A., 2012. Status of genomic imprinting in epigenetically distinct pluripotent stem cells. Stem Cells, 30 (2), pp. 161-168.
Murrell, A., 2011. Setting up and maintaining differential insulators and boundaries for genomic imprinting. Biochemistry and Cell Biology, 89 (5), pp. 469-478.
Huntriss, J., Woodfine, K., Huddleston, J. E., Murrell, A., Rutherford, A. J., Elder, K., Khan, A. A., Hemmings, K. and Picton, H., 2011. Quantitative analysis of DNA methylation of imprinted genes in single human blastocysts by pyrosequencing. Fertility and Sterility, 95 (8), 2564-2567.e8.
Nativio, R., Sparago, A., Ito, Y., Weksberg, R., Riccio, A. and Murrell, A., 2011. Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome. Human Molecular Genetics, 20 (7), pp. 1363-1374.
Ibrahim, A. E. K., Arends, M. J., Silva, A.-L., Wyllie, A. H., Greger, L., Ito, Y., Vowler, S. L., Huang, T. H.-M., Tavaré, S., Murrell, A. and Brenton, J. D., 2011. Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. Gut, 60 (4), pp. 499-508.
Sandovici, I., Smith, N. H., Nitert, M. D., Ackers-Johnson, M., Uribe-Lewis, S., Ito, Y., Jones, R. H., Marquez, V. E., Cairns, W., Tadayyon, M., O'Neill, L. P., Murrell, A., Ling, C., Constância, M. and Ozanne, S. E., 2011. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proceedings of the National Academy of Sciences of the United States of America, 108 (13), pp. 5449-54.
Woodfine, K., Huddleston, J. E. and Murrell, A., 2011. Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenetics & Chromatin, 4 (1), 1.
Uribe-Lewis, S., Woodfine, K., Stojic, L. and Murrell, A., 2011. Molecular mechanisms of genomic imprinting and clinical implications for cancer. Expert Reviews in Molecular Medicine, 13, e2.
Farrar, D., Rai, S., Chernukhin, I., Jagodic, M., Ito, Y., Yammine, S., Ohlsson, R., Murrell, A. and Klenova, E., 2010. Mutational analysis of the poly(ADP-ribosyl)ation sites of the transcription factor CTCF provides an insight into the mechanism of its regulation by poly(ADP-ribosyl)ation. Molecular and Cellular Biology, 30 (5), pp. 1199-1216.
Frost, J. M., Monk, D., Stojilkovic-Mikic, T., Woodfine, K., Chitty, L. S., Murrell, A., Stanier, P. and Moore, G. E., 2010. Evaluation of allelic expression of imprinted genes in adult human blood. PLoS ONE, 5 (10), e13556.
Nativio, R., Wendt, K. S., Ito, Y., Huddleston, J. E., Uribe-lewis, S., Woodfine, K., Krueger, C., Reik, W., Peters, J.-M. and Murrell, A., 2009. Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus. Plos Genetics, 5 (11), e1000739.
Watson, J. A., Watson, C. J., McCrohan, A.-M., Woodfine, K., Tosetto, M., McDaid, J., Gallagher, E., Betts, D., Baugh, J., O'Sullivan, J., Murrell, A., Watson, R. W. G. and McCann, A., 2009. Generation of an epigenetic signature by chronic hypoxia in prostate cells. Human Molecular Genetics, 18 (19), pp. 3594-3604.
Ito, Y., Koessler, T., Ibrahim, A. E. K., Rai, S., Vowler, S. L., Abu-Amero, S., Silva, A.-L., Maia, A.-T., Huddleston, J. E., Uribe-Lewis, S., Woodfine, K., Jagodic, M., Nativio, R., Dunning, A., Moore, G., Klenova, E., Bingham, S., Pharoah, P. D. P., Brenton, J. D., Beck, S., Sandhu, M. S. and Murrell, A., 2008. Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Human Molecular Genetics, 17 (17), pp. 2633-2643.
Murrell, A., Ito, Y., Verde, G., Huddleston, J., Woodfine, K., Silengo, M. C., Spreafico, F., Perotti, D., De Crescenzo, A., Sparago, A., Cerrato, F. and Riccio, A., 2008. Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer. PLoS ONE, 3 (3), e1849.
Tomazou, E. M., Rakyan, V. K., Lefebvre, G., Andrews, R., Ellis, P., Jackson, D. K., Langford, C., Francis, M. D., Bäckdahl, L., Miretti, M., Coggill, P., Ottaviani, D., Sheer, D., Murrell, A. and Beck, S., 2008. Generation of a genomic tiling array of the human major histocompatibility complex (MHC) and its application for DNA methylation analysis. BMC Medical Genomics, 1, 19.