Feature Human Epigenome Project—Up and Running Jane Bradbury pigenomics is one of the are switched on and off to produce a many ‘omics’ that is being person. And knowing more about the The Human Genome Project Etalked about in the wake of human epigenome may provide clues the Human Genome Project. But to what goes wrong in cancer and other … ‘provided the blueprint, what is an epigenome, and why have diseases. the Wellcome Trust Sanger Institute for life but the epigenome What Is Epigenetics? (Hinxton, United Kingdom) and will tell us how this whole Epigenomics AG (Berlin, Germany) Most people have a fair idea of what recently announced the launch of the is meant by genetics. They know that thing gets executed’. Human Epigenome Project (HEP), characteristics such as eye colour are a fi ve-year undertaking during which specifi ed by the DNA sequence within DNA methylation sites throughout their genome. But not everything is That ‘something else’ is chemical the human genome will be mapped? that simple. For example, genetically modifi cations of genes that are The HEP is the brainchild of identical twins can be very different. heritable from one cell generation immunogeneticist Stephan Beck of the ‘One might be normal, while the to the next and that affect gene Sanger Institute and Alexander Olek, other is autistic’, explains chromatin expression but do not alter the DNA chief executive offi cer of Epigenomics researcher David Allis (Rockefeller sequence. Epigenetic modifi cations can AG. The Human Genome Project, University, New York, United States). affect the DNA itself or the proteins explains Olek, ‘provided the blueprint ‘We can’t explain that on the basis that package the DNA into chromatin. for life, but the epigenome will tell us of pure genetics because the DNA is Developmental geneticist Wolf Reik how this whole thing gets executed’, identical. Something else must be at (The Babraham Institute, Cambridge, what determines when and where genes play’. United Kingdom) describes these modifi cations as ‘red and green traffi c lights that are superimposed on top of the genome to tell the genes whether Box 1. The Same but Different they should be active or inactive’. For Geneticist Emma Whitelaw (University of Sydney, Australia) studies phenomena in mice similar individual cells, this code on top of a to those seen in human monozygotic twins, whereby genetically identical individuals can look code helps to determine whether a cell or behave very differently. About a decade ago, she explains, ‘we noticed that in a litter of mice is a blood cell, a fat cell, or something that had all stably inherited a transgene at a specifi c locus, some mice expressed the transgene, else. And in the case of monozygotic but others didn’t’. This variable gene expressivity in genetically identical animals suggested that twins, unexpected differences may some kind of epigenetic mark had occurred differentially between individuals by chance. Similarly, result from chance variations in this identical mice carrying the agouti viable yellow coat colour gene can range in colour from yellow superimposed code (Box 1). through mottled to brown, depending on whether the gene is expressed or not. And while a The study of these modifi cations— mutation in the axin gene called axin-fused produces mice with kinky tails, the degree of kinkiness what they are, how they are laid varies among genetically down, and the processes that they identical littermates (Figure 1). control—is the fi eld of research known For all these mice, Whitelaw as epigenetics. An epigenome is the has discovered that the description of these modifi cations mysterious epigenetic marks across the whole genome, but unlike responsible for variable the genome DNA sequence, each expressivity are inherited organism has multiple epigenomes— between sexual generations. for example, in different cell types— So, in the case of the agouti viable yellow mice, yellow mice Copyright: © 2003 Jane Bradbury. This is an open- have more yellow offspring access article distributed under the terms of the than mottled or brown Creative Commons Attribution License, which offspring. Variable expressivity permits unrestricted use, distribution, and reproduction in any medium, provided the original may be a quicker way to deal work is properly cited. with environmental change than DNA mutation and, Abbreviations: HEP, Human Epigenome Project; MHC, DOI: 10.1371/journal/pbio.0000082.g001 major histocompatibility complex suggests Whitelaw, it may Figure 1. Spot the Difference: Same Genes but a Different Kink be that variable expressivity Jane Bradbury is a freelance science news in the Tail writer based in Cambridge, United Kingdom. E-mail: is involved in some way in (Photograph courtesy of Emma Whitelaw, University of [email protected] evolution. Sydney, Australia.) DOI: 10.1371/journal/pbio.0000082 PLoS Biology | http://biology.plosjournals.org Volume 1 | Issue 3 | Page 316 that may change during its lifetime in enormous undertaking. ‘Knowing the DNA methylation sites throughout the response to environmental cues. methylation sequence’, says Bird, ‘will entire MHC region, the consortium be an essential backdrop to future set out to look at the 150 expressed DNA Methylation research on DNA methylation and its genes within this region, explains Beck. Methylated DNA was the fi rst biological effects’. Allis agrees that For each gene, the scientists chose epigenetic mark to be discovered. DNA methylation is an important part two areas to analyse for methylation, That this epigenetic modifi cation is of epigenetic marking, but ‘although each about 500 basepairs long. ‘One important is suggested by the waves mapping DNA methylation patterns is window was in what we thought was of demethylation and de novo (new) the logical and good place to start, by the promoter region’, says Beck, methylation that occur at specifi c its lonesome it won’t explain the whole ‘and the other corresponded to the stages during the development of an epigenetic phenomenon’. most CpG-rich region in the gene’. animal from a fertilised egg. Soon Beck and Olek began thinking about The promoter regions are the places after fertilisation, there is a massive mapping the human epigenome more where the elements that control gene active loss of methylation from the than fi ve years ago. Even as long ago expression are often located, and DNA paternal genome, explains Reik. At the as 1998, explains Olek, ‘it was pretty methylation occurs at cytosine residues same time, the maternal genome loses natural to be thinking about what within CpG motifs, hence the choice of some methyl groups through passive would come after the Human Genome CpG-rich regions. demethylation. ‘We think this process Project, and Stephan believed that The methylation status of more erases all the epigenetic memory in the it had to be methylation sequencing than 100, 000 sites was determined gametes [sperm and egg cells] except because that has the potential to tell during the three-year pilot study and for some special imprinted genes whose us about the hundreds of genomes we the results analysed to show where expression depends on whether they really have’. there were methylation differences are of maternal or parental origin’, says In October 2000, the Human in the MHC between different Reik. Later in development, widespread Epigenome Consortium (the Sanger tissues (Figure 2). ‘We found major de novo DNA methylation occurs in a Institute, Epigenomics AG, and the methylation differences between loci process known as reprogramming. De Centre National de Génotypage in and between tissues’, says Beck, ‘and novo methylation rarely occurs after Evry, France) started a European we are particularly interested in what an early developmental event known Union-funded pilot project to map we call methylation variable positions as gastrulation, except in cancer cells the methylation sites within the major (MVPs), which we believe will advance where special unmethylated regions histocompatibility complex (MHC) our ability to understand and diagnose of the genome, known as CpG islands, region in seven different human human disease’. Olek echoes Beck’s often become methylated. tissues. Rather than look at all the satisfaction with the results to date. ‘We ‘People generally agree that DNA methylation is important for imprinting and reprogramming’, says Reik, ‘but not everyone agrees that it plays a role in DNA activation and inactivation during development’, a role fi rst proposed more than 25 years ago. ‘People are still hesitant about saying that DNA methylation is important in making sure the right genes are expressed in the right cells at the right time because until recently we have had relatively few good examples’, says DNA methylation expert Adrian Bird (The Wellcome Trust Centre for Cell Biology, Edinburgh, United Kingdom). Many people have reported correlations between methylation states and gene activity but, says Reik, ‘you can look at such correlations until the cows come home and it tells you nothing about causality’. The HEP Pilot DOI: 10.1371/journal/pbio.0000082.g002 Even given the doubts about the Figure 2. Example of HEP Methylation Data for the BAT8 Gene, an MHC-Linked Histone exact role of DNA methylation, Bird, Methyltransferase Allis, and Reik believe that mapping In this case, two regions marked in red were analysed in 31 samples (rows) from seven tissues (blocks of rows). The predicted structure of the gene is shown below with methylation patterns across the coloured boxes indicating the exons. As part of the launch of the HEP on October 7, human genome, which is what the 2003, these data and others, together with experimental details of the pilot study, were HEP plans to do, is a worthwhile albeit released at www.epigenome.org. PLoS Biology | http://biology.plosjournals.org Volume 1 | Issue 3 | Page 317 can see that there is hidden treasure in way’.