A blueprint for a human epigenome project : The AACR human epigenome workshop
15 Dec 2005-Cancer Research (American Association for Cancer Research)-Vol. 65, Iss: 24, pp 11241-11246
TL;DR: A timely workshop of leading experts confirmed that the technology is at hand to begin defining human epigenomes at high resolution.
Abstract: Epigenetic processes control the packaging and function of the human genome and contribute to normal and pathologic states, including cancer. The time is ripe to undertake an international effort to identify all the chemical changes and relationships between chromatin constituents that provide function to the genetic code. A timely workshop of leading experts, convened by the American Association for Cancer Research (AACR), confirmed that the technology is at hand to begin defining human epigenomes at high resolution.
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TL;DR: The current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies are discussed.
Abstract: Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
4,033 citations
Cites background from "A blueprint for a human epigenome p..."
...These findings have led to a global initiative to understand the role of epigenetics in the initiation and propagation of cancer [7]....
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TL;DR: This account of epigenetics in cancer reviews the mechanisms and consequences of epigenetic changes in cancer cells and concludes with the implications of these changes for the diagnosis, prognosis, and treatment of cancer.
Abstract: Gene transcription can be activated or inhibited by a reversible modification of the gene; this modification is termed an epigenetic change. This account of epigenetics in cancer reviews the mechan...
3,150 citations
TL;DR: It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.
Abstract: An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide — an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.
2,080 citations
Cites background from "A blueprint for a human epigenome p..."
...Calls have been made for a comprehensive human epigenome project, with the aim of cataloguing genome-wide profiles for an extensive range of epigenetic marks in various human cell types, as well as in some of the key animal models for human development and diseas...
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TL;DR: Current research efforts are reviewed, with an emphasis on large-scale studies, emerging technologies, and challenges ahead.
2,035 citations
Cites background from "A blueprint for a human epigenome p..."
...We note recent discussions about an ‘‘epigenome project’’ that would produce draft analyses of cytosine methylation, key histone modifications and variants, and chromatin-associated proteins in carefully chosen cell states (Jones and Martienssen, 2005; Qiu, 2006)....
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...Although it has been suggested that most CpG islands are always unmethylated, a subset have been shown to be subject to tissuespecific methylation during development (Bird, 2002; Strichman-Almashanu et al., 2002)....
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TL;DR: Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation.
Abstract: DNA methylation constitutes the most stable type of epigenetic modifications modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation reference profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of 6 annotation categories, revealed evolutionary conserved regions to be the predominant sites for differential DNA methylation and a core region surrounding the transcriptional start site as informative surrogate for promoter methylation. We find 17% of the 873 analyzed genes differentially methylated in their 5′-untranslated regions (5′-UTR) and about one third of the differentially methylated 5′-UTRs to be inversely correlated with transcription. While our study was controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.
1,335 citations
Cites background from "A blueprint for a human epigenome p..."
...Toward this goal, a blueprint for an international human epigenome project (recently dubbed the Alliance for Human Epigenomics and Disease (AHEAD)) has been propose...
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References
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TL;DR: Analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles, tissue specificity, inter-individual variation, and correlation with independent gene expression data.
Abstract: The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine-guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated), tissue specificity, inter-individual variation, and correlation with independent gene expression data.
352 citations
"A blueprint for a human epigenome p..." refers methods in this paper
...In a pilot phase of the European HEP, published in November 2004 (2), the effort successfully analyzed 253 loci covering 90 genes within the human MHC by bisulfite sequencing, identifying methylation variable positions in six tissue types....
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TL;DR: The results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.
Abstract: Aberrant methylation of CpG islands and genomic deletion are two predominant mechanisms of gene inactivation in tumorigenesis, but the extent to which they interact is largely unknown. The lack of an integrated approach to study these mechanisms has limited the understanding of tumor genomes and cancer genes. Restriction landmark genomic scanning (RLGS; ref. 1) is useful for global analysis of aberrant methylation of CpG islands, but has not been amenable to alignment with deletion maps because the identity of most RLGS fragments is unknown. Here, we determined the nucleotide sequence and exact chromosomal position of RLGS fragments throughout the genome using the whole chromosome of origin of the fragments2 and in silico restriction digestion of the human genome sequence. To study the interaction of these gene-inactivation mechanisms in primary brain tumors, we integrated RLGS-based methylation analysis with high-resolution deletion maps from microarray-based comparative genomic hybridization (array CGH; ref. 3). Certain subsets of gene-associated CpG islands were preferentially affected by convergent methylation and deletion, including genes that exhibit tumor-suppressor activity, such as CISH1 (encoding SOCS1; ref. 4), as well as genes such as COE3 that have been missed by traditional non-integrated approaches. Our results show that most aberrant methylation events are focal and independent of deletions, and the rare convergence of these mechanisms can pinpoint biallelic gene inactivation without the use of positional cloning.
180 citations
"A blueprint for a human epigenome p..." refers background or methods in this paper
...1), 66% were due to methylation, 18% were due to deletion, and 7% showed deletion of one allele and methylation of the other (1)....
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...Modified and reproduced with permission of Nature Genetics (1)....
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