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Project Title: Complexity of Interdependent Epigenetic Signals in Cancer Initiation (CIESCI)


Link to calendar of events for CIESCI Project


Researchers Names and Affiliations:

Heather J. Ruskin (contact) and Dimitri Perrin (contact), Centre for Scientific Computing and Complex Systems Modelling, (Sci-Sym), Dublin City University, Glasnevin, Dublin 9, Ireland.
Manel Esteller (contact) and Dori Huertas (contact), Bellvitge Institute for Biomedical Research, (IDIBELL), Barcelona, Spain.
Jaak Vilo (contact), Bioinformatics, Algorithmics, and Data Mining Research Group (BIIT), Inst. of Computer Science and Estonian Biocenter, University of Tartu, Liivi 2, 50409 Tartu, Estonia


Project Overview:

Recent biomedical research has shown that phenotype of living organisms depends on complex interdependent mechanisms, deriving not only from genotypical and environmental, but also from a large set of interactions modifying gene expression without alteration of the DNA sequence, a phenomenon called Epigenetics. Epigenetic mechanisms involve heritable alterations in chromatin structure, (e.g. DNA methylation and histone acetylation), amongst other epigenetic “signatures”. In turn these regulate transcriptional activation of protein- and RNA-encoding genes (gene expression). Epigenetic signals are not observable from raw genomic DNA sequence alone, since they do not involve changes in coding. Nevertheless, these “stable and dynamic alterations” arise during development and cell proliferation and persist through cell division. While information within the genetic material is not changed, instructions for its assembly and interpretation may be.

Alterations in DNA methylation, imprinting and chromatin structure are common in cancer [2-6], and links to epigenetic changes have been established in several cases, e.g. in Wilm's tumour and colon cancer. Epigenetic mechanisms are also studied in other medical fields because of association with obesity, abnormal neural development, mood disorders such as stress vulnerability and bipolar disorder, or risk of heart failure. The balance of DNA methylation is altered in human cancers: there is hypomethylation of repetitive sequences that account for chromosomal instability, and hypermethylation of CpG islands in the promoters of tumour-supressor genes, which is a major event in the origin of many cancers. The key enzymes that regulate the balance of DNA methylation are DNA methylatransferases (DNMTs), which introduce methyl groups to DNA, and methyl-CpG-binding domain proteins (MBDs), which recognize and bind DNA methyl groups. 1 Laboratory research on epigenetic mechanisms is costly, time-consuming, and, of necessity focused on investigation of specific changes. Consequently, technical constraints mean that explanation of system-wide complex interactions is out of reach.

The capability of hybridised models, combining agent-based and network approaches to bridge scale transitions and it is this novel multi-layered approach that we aim to bring to the present problem. Bioinformatics methods: e.g. on management and analysis of massive datasets, in the international context and on development of bioinformatics methods and tools, spanning a range of data types, and novel data being captured by researchers at IDIBELL. Their ground-breaking work, focuses in particular on a comprehensive study of the epigenome-wide profile that integrates DNA methylation and histone modification, as well as chromatin modifier enzymes during different stages of cancer initiation and progression.

Keywords: Complex biomedical system; gene expression; Epigenetics; cancer initiation


Project Goals:

The overall objective of this study is, therefore, to investigate the interactions of DNMTs and MBDs, as well as histone modification enzymes, implicated in cancer initiation. This will be achieved through efforts on three interconnected layers, namely:

(A) wet-lab experiments,
(B) bioinformatics assisted analysis,
(C) computer-based modelling.

No such large-scale, inter-disciplinary, efforts on epigenetic research, across multiple scales, have been reported in the scientific literature to date. These three layers are intrinsically interconnected. Hypothesis formulation on correlations between elements of the epigenome profile will result from the first two layers, analysis carried out through layers (B) and (C) will lead to new experiments, while validation of the formulated hypotheses will involve all three layers. Additionally, computer-based modelling of these epigenetic profiles can provide a potent tool to understand and predict how genes are targeted for aberrant methylation. There are four epigenetic mechanisms that modify chromatin structure: DNA methylation, histone modification, histone variants and nucleosome remodeling, and non-coding RNAs. The cancer epigenome is characterised by global changes in DNA methylation and histone modification patterns, as well as altered expression profiles of chromatin-modifying enzymes. However, events that lead to initiation of these epigenetic abnormalities are still not understood.


Scientific Track Record of Participants:


Manel Esteller and his group at the Bellvitge Institute for Biomedical Research, (IDIBELL), are leaders in research on Epigenetics and cancer, and will take responsibility for work described in layer (A). Their previous work has led to over 50 publications in leading international journals in the last three years, including articles in Nature Genetics, Science, Nucleic Acids Research and Oncogene. Since October 2008, Dr Esteller has been Director of the Cancer Epigenetics and Biology Program of the Bellvitge Institute for Biomedical Research in Barcelona and leader of the Cancer Epigenetics Group.

Jaak Vilo and his group at the University of Tartu have a solid expertise in bioinformatics, in particular in its application to gene expression and regulation data-mining cancer-related studies, and are therefore well-equipped to take care of layer (B). Experience includes gene expression data analysis, biological data mining, combinatorial pattern matching, and software development for biomedical research databases. Existing tools (g:Profiler, MEM, GraphWeb, KEGGanim, FunGenES atlas, ESCD) provide crucial experience, and may also be adapted to the context of this study. Current projects include participation EU FP6 STREP “Colon and Breast cancer Diagnostics” and a NoE ENFIN.

Heather J. Ruskin, Dimitri Perrin and the Sci-Sym Centre at Dublin City University provide well recognised expertise in analysing and modelling complex systems, in particular in the biomedical but also social context, and will focus on layer (C). They are currently developing a multi-approach model of epigenetic changes, (funded by Science Foundation Ireland under the Research Frontiers Program). This study is the first attempt, worldwide, to directly model these interactions, and includes a representation of infection-induced aberrant DNA methylation in gastric cells, developed in collaboration with the National Cancer Center (Tokyo, Japan), and used as a proof of concept for the present proposal.


Last Updated ( Monday, 21 February 2011 15:51 )
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