This finding will have an impact on our understanding of the origins of individual phenotypic differences and will have implications for future genetic studies of complex disease.
The February 2010 issue of the American Journal of Human Genetics includes a paper that describes the first quantitative genomic survey of allele-specific DNA methylation, where investigators used sensitive high-throughput technology to search for evidence of skewed gene DNA methylation across both alleles of the DNA sequence.
The investigators of the study, from the Institute of Psychiatry (IOP; King‘s College London, UK), used SNP microarrays to quantitatively assess allele-specific DNA methylation in amplicons covering 7.6% of the human genome following cleavage with a mixture of methylation-sensitive restriction enzymes. They also verified some selected findings in a subsequent second tissue from the same individuals using bisulfite-mapping and gene-expression analyses, and then replicated this again in DNA obtained from 30 parent–child trios.
Lead researcher of the study Dr Jonathan Mill, Medical Research Council Social Genetic, Developmental and Psychiatry Centre at the IOP enthused that, “Interestingly, we found numerous examples where DNA methylation was not equal across alleles – in some instances this depended upon genotype, and in other cases it depended upon which parent that allele was inherited from. Our data show that allele-specific DNA methylation is a widespread phenomenon with potentially over 35,000 such sites occurring across the genome. It appears that a spectrum of skewing is likely, differing between individuals and across tissues”.
From the analysis of the results, they were able to identify numerous novel regions of the genome, where the chemical modifications involved in controlling gene expression are either influenced by genetic variation or the parental origin of that particular stretch of DNA. These findings, in fact, contradict previous assumptions that epigenetic signals are generally equal across both copies of a given region of the genome, except at a small number of known imprinted genes.
Dr Mill concludes by stating that, “These findings impact upon our understanding about the origin of biological variation and have implications for genetic studies of complex disease, including most psychiatric conditions. Since DNA methylation can also be influenced by various environmental factors, the variation we have uncovered provides a potential substrate for interactions between nature and nurture”.
Source: Schalkwyk LC, Meaburn EL, Smith R et al.: Allelic skewing of DNA methylation is widespread across the genome. Am. J. Hum. Genet. 86(2), 196–212 (2010).
Bisphenol-A (BPA) is a nonsteroidal estrogen that is ubiquitous in the environment and found in common plastics that are used to contain food and other materials. For example, they are used in water bottles, baby bottles, epoxy resins used to coat food cans and dental sealants. BPA, which has been thought to be a ‘safe‘ plastic, has now been implicated in causing changes to the epigenetic regulation of female fetuses in pregnant mice that may lead to permanent reproduction problems. This study, which was recently published in the FASEB Journal, suggests that there may be a link between BPA and disruption to epigenetic mechanisms in utero.
Scientists from Yale University School of Medicine (CT, USA) set out to study the epigenetic mechanism underling BPA-mediated alterations in Hoxa10 expression in pregnant mice. “Exposure to BPA may be harmful during pregnancy; this exposure may permanently affect the fetus”, explained Dr Hugh S Taylor, co-author of the study from Yale University School of Medicine. “We need to better identify the effects of environmental contaminants on not just crude measures such as birth defects, but also their effect in causing more subtle developmental errors”.
The research group from Yale discovered this link by exposing fetal mice to BPA during pregnancy and then examining the gene-expression patterns and DNA from the uteri of the female fetuses. The results that they accumulated from their experiments demonstrated that BPA exposure permanently affected the uterus by decreasing gene-expression regulation.
Bisphenol-A was demonstrated to induce epigenetic changes that caused the exposed mice to over-respond to estrogen throughout their adulthood, despite the fact that they were exposed to BPA only in utero.
Therefore, the results of this study suggest that early exposure to BPA genetically reprogrammed the uterus to be hyper-responsive to estrogen. Fertility problems, advanced puberty, altered mammary development and reproductive function, as well as a variety of hormone-related cancers have been linked to extreme estrogen sensitivity (similar to the effect that has been demonstrated with BPA exposure). However, this preliminary finding needs to be confirmed through further studies.
Source: Bromer JG, Zhou Y, Taylor MB, Doherty L, Taylor HS: Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J. (2010) (Epub ahead of print).
Cancer genomic research is being propelled forward with the advent of the newest high-throughput DNA sequencing technologies that are helping to reveal the inner molecular workings of the cancer genome. Melanoma research, for example, has recently been in the spotlight owing to the publication of a paper in the journal Genome Research. This paper reports on how a team of researchers were able to investigate the melanoma RNA transcriptome using the application of high-throughput sequencing technology.
The team, which consisted of researchers from The Broad Institute of MIT and Harvard (MA, USA), set out to perform an integrative analysis of melanoma tumors using RNA sequencing and structural genomic data. From their studies, the group was able to identify 11 novel gene fusions involving several common cancer-related genes, and 12 cases of chimeric transcripts from the melanoma tumor samples. “This is the first direct evidence for these types of genetic alterations in melanoma”, commented Michael Berger, lead author and research scientist at the Broad Institute.
The authors suggest that this type of cancer transcriptome analysis complements the common DNA-based genomic sequencing and characterization approaches that are used to capture a more complete picture of the cancer genome, and is therefore a very appealing technique for cancers researchers to incorporate into their research.
Levi Garraway, the study‘s senior author and Assistant Professor at Harvard Medical School/Dana–Farber Cancer Institute (MA, USA) concluded that, “Such studies should help reveal the cancer RNA world, thereby nominating many new genetic targets relevant to tumor biology and drug discovery”.
Source: Berger MF, Levin JZ, Vijayendran K et al.: Integrative analysis of the melanoma transcriptome. Genome Res. (2010) (Epub ahead of print).
A protein called AID has been pinpointed in a study carried out by researchers from Babraham Institute (Cambridge, UK) as being important for complete cellular reprogramming in mammals. The findings, published online in the journal Nature, may provide vital clues for the reversing of cell fate and could advance the field of regenerative medicine and pave the way for novel therapeutics.
Prof Wolf Reik, Associate Director at the Babraham Institute and Professor of Epigenetics at the University of Cambridge (Cambridge, UK) who led the research explained that, “With numerous human, animal and plant genomes now sequenced, a key question is how genomes are regulated in normal development, health and disease. Altered regulation of the epigenome is likely to underlie many human diseases so unlocking the principles of reprogramming can be harnessed to benefit regenerative medicine and stem cell therapy”.
This study revealed that AID plays a role in erasing the chemical marks that appear on the genome as an embryo develops, and determining what a particular cell‘s identity will be. It appears that AID is also involved in removing the epigenetic tags from DNA by demethylation, known to be a critical component of cellular reprogramming. This research is corroborated by another study, which also identifies AID as being important for reprogramming, that was also recently published in the journal Natureand was carried out by Dr Helen Blau‘s laboratory in Stanford (CA, USA).
This collaboration between scientists at Babraham, the Howard Hughes Medical Institute (MD, USA) and University of California at Los Angeles (UCLA; CA, USA) reveals for the first time the extent to which the erasure of epigenetic tags occurs in mammals, erasing the epigenome between generations. Professor Reik commented that, “Whole epigenomes can now be unravelled and understood thanks to next-generation sequencing technology, which we used in collaboration with the UCLA team, and which we also have at the Babraham, a partner in the East Anglia Sequencing and Informatics Hub”.
It was thought that, as the embryo develops, the Aid gene is normally switched on. However, the Babraham team found that if the AID protein is missing in cells, the methylation patterns are not completely cleared and an epigenetic memory is thus inherited. Reik commented on this finding, “Clear mechanisms for DNA demethylation have been elusive for some time. The body of evidence is now pointing to indirect demethylation through the action of key enzymes such as AID”.
The Babraham team is now also going to pursue the possible commercial application of this protein in collaboration with the company CellCentric (Cambridge, UK).“Epigenetics is a growing area of academic research and commercial development. By understanding what proteins cause cell-fate change, new tools and methods can be designed for both regenerative medicine and the treatment of intractable diseases. Specifically, the identification of AID and its activity may offer the ability to test the importance of gene-specific demethylation, as well as the potential to overcome a pivotal epigenetic barrier in reprogramming cells for induced pluripotent cell production”, explained Dr Will West, chief executive officer of CellCentric.
Sources: Popp C, Dean W, Suhua Feng S et al.: Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 463(7284), 1101–1105 (2010);
Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM: Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463(7284), 1042–1047 (2010).