23rd November 2004

Genomic Bookmarks Uncovered

First Chapter of Human Epigenome Project

Genomic Bookmarks Uncovered

Genomic Bookmarks Uncovered

Somewhere, we all have a textbook from school with pencilled notes in the margin which tell us which bits should be remembered and which bits we can forget. Sometimes, we change our minds and erase the notes, or add new ones. Our friends make different notes and remember different key passages.

The 'Book of Life' - the human genome - carries equivalent marks on the letters of DNA code - chemical marks that help our cells to know which bits should be active and which bits are not to be used.

For our genome to function correctly, sequence alone is not sufficient. It is marked by addition of methyl groups to cytosine bases in DNA. As well as altering activity of genes, methylation of DNA can have consequences for development and diseases such as cancer.

Apart from a few genes, the methylation profile of human DNA is poorly understood but, with completion of the Human Genome Project, it now becomes possible to determine the effects of methylation on a global, genome-wide scale. The goal of the Human Epigenome Project (HEP), a collaboration between The Wellcome Trust Sanger Institute, Epigenomics AG and The Centre National de Génotypage, is to define methylation on a scale never attempted before and to investigate fully its role in health and disease.

The Pilot study for the HEP - the first systematic analysis of methylation - is published on Tuesday 23 November 2004 in PLoS Biology. The Consortium proved that their novel approach is highly successful in detecting these subtle changes and that differences between individuals and tissues samples can be readily detected. The systems are now in place to complete the first study of the entire human epigenome.

"Application of high-throughput analysis to detect subtle changes like those found in methylation was a tremendously challenging task," said Dr Stephan Beck, the Project's Principal Investigator at The Wellcome Trust Sanger Institute, "but the MHC is an ideal model for understanding the entire human epigenome. In a very short time, we have moved these technologies from testing grounds to a position of being able to tackle the entire genome and get detailed and global understanding of the role that methylation plays in health and disease."

The team have focused on a region of the genome that is involved many diseases and is rich in genes - the Major Histocompatability Complex (MHC). As well as a role in the immune system, the MHC is also involved in diseases from diabetes to arthritis.

Regions of genes and regions that control genes were studied using two techniques: there is existing evidence that methylation of control regions modifies the activity of the affected gene. Looking at more than 250 regions of 90 genes (about 0.4% of all human genes), both methods showed that, most often, the samples either had very little methylation or were almost fully methylated.

"The Human Genome Project has produced the foundation for new biomedical research. Our challenge as scientists is to translate that knowledge into real benefit. The epigenome is a key to unlocking the secrets of many diseases," said Dr Kurt Berlin, the Project's Principal Investigator and Chief Scientific Officer at Epigenomics AG. "Already our results indicate intriguing levels of variation in the human epigenome and with the continued production of results new ways to look at genes and disease are emerging."

Specific differences in methylation were found among tissues and individuals. For example, a gene called TNXB involved in limb, heart and muscle development was methylated in most tissues except muscle, suggesting lack of methylation is important for the activity of TNXB in this tissue. However, the study suggests that, for many genes, we need a better understanding of their activity, a major focus of projects at The Wellcome Trust Sanger Institute and other institutions.

Across the range of tissues tested, high levels of methylation at predicted control regions were correlated with low levels of gene activity and high gene activity correlated with low levels of methylation. The Pilot phase has established that bases of DNA code that are subject to different levels of methylation in different tissues or different individuals can be detected in a systematic fashion.

From now, it becomes possible truly to examine the role of methylation in gene activity and, most important, in human disease such as cancer where there is already evidence that methylation plays a role in disease and prognosis.

Phase I of the HEP, based on the findings reported today, is already underway to analyse some 10% of all human genes, using 20 tissue types from more than 40 people.

Methylation changes have been found in a wide range of diseases including:

  • Colon cancer (IGF2, chromosome 11)

  • Prader-Willi syndrome (PWS region, chromosome 15)

  • Rett syndrome (MECP2 gene, X chromosome)

  • Fragile X mental retardation syndrome (FMR1, X chromosome)

  • Beckwith-Wiedemann syndrome (BWS; several genes, including IGF2 and CDKN1C, chromosome 11)

Notes to Editors

About the HEP

  1. The Human Epigenome Project (HEP) aims to identify, catalogue and interpret genome-wide DNA methylation patterns of all human genes in all major tissues. Methylation is the only flexible genomic parameter that can change genome function under exogenous influence. Hence it constitutes the main and so far missing link between genetics, disease and the environment that is widely thought to play a decisive role in the aetiology of virtually all human pathologies. Methylation occurs naturally on cytosine bases at CpG sequences and is involved in controlling the correct expression of genes. Differentially methylated cytosines give rise to distinct patterns specific for tissue type and disease state. Such methylation variable positions (MVPs) are common epigenetic markers. Like single nucleotide polymorphisms (SNPs), they promise to significantly advance our ability to understand and diagnose human disease.

  2. The Human Epigenome Project (HEP) is a public/private collaboration run by the members of the Human Epigenome Consortium. MVPs identified as part of the HEP will be released publicly in accordance with the HEP data release policy.

  3. The partners in the Human Epigenome Consortium are:

    • The Wellcome Trust Sanger Institute, a recognised leader in genome sequencing, high-throughput systems, informatics and analysis of gene function using genetic approaches in a variety of model organisms and humans.

    • Epigenomics AG, a transatlantic biotechnology company with headquarters in Berlin, Germany and its wholly owned subsidiary in Seattle, Washington, USA. Epigenomics AG is pioneering tomorrow's personalized medicine by exploiting the information of DNA methylation patterns.

    • The Centre National de Génotypage, a national research institute set up in 1998 by the French Government in anticipation of using the genome sequencing information for the identification of genes and gene function.

  4. Publication details

    • DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project.

      Rakyan VK, Hildmann T, Novik KL, Lewin J, Tost J, Cox AV, Andrews TD, Howe KL, Otto T, Olek A, Fischer J, Gut IG, Berlin K and Beck S

      PLoS biology 2004;2;12;e405


The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.


The Wellcome Trust and Its Founder

The Wellcome Trust is the most diverse biomedical research charity in the world, spending about £450 million every year both in the UK and internationally to support and promote research that will improve the health of humans and animals. The Trust was established under the will of Sir Henry Wellcome, and is funded from a private endowment, which is managed with long-term stability and growth in mind.


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