‘Epigenetic fingerprints‘ provide clues to understanding many of the human body processes and how these processes lead to disease.
A groundbreaking study that investigated the DNA methylation profiles of 1628 people including healthy volunteers and patients suffering from common diseases, such as cancer and cardiovascular and neurodegenerative diseases has been published in the journal, Genome Research. The vast team of scientists coordinated by Professor Manel Esteller, director of the Epigenetics and Cancer Biology Program of the Bellvitge Biomedical Research Institute, professor at the University of Barcelona and Institució Catalana de Recerca i Estudis Avançats (Spain), set out to identify the DNA methylation patterns across one of the largest spectrum of samples, tissues and diseases reported to date.
Speaking to Epigenomics, Esteller explained that “The article represents the largest collection of human samples ever studied for DNA methylation at a global genomic level. I think that it will be appealing to a large community of biomedical researchers and physicians because it includes different types of ‘normal‘ cells/tissues and distinct types of diseases. Among the first, the obtained DNA methylation fingerprints show that every differentiated tissue has its own profile of DNA methylation, that a differentiated tissue derived from a stem cell retains some stem-like DNA methylation marks and that the DNA methylation landscape changes with age”. Their findings provide important clues regarding the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases. It is hoped that this study can help develop higher-resolution DNA methylation maps.
The researchers also identified distinct patterns of DNA methylation in brain tissues from patients with dementia and in blood cells of patients with autoimmune disorders such as lupus. Esteller commented that “Among other disorders, the study also shows that a form of human dementia (Lewy bodies dementia) and the autoimmune disorder systemic lupus erithematosus each had alone a characteristic DNA methylation landscape, where hypomethylation events are prevalent”.
Christoph Bock, coauthor and Research Group Leader, Computational Epigenetics Group, Max-Planck-Institut Informatik (Germany) on discussing the novelty of this study with Epigenomics explained: “I guess with any research project you can go for depth or for breadth. Both approaches have value, and there have been a number of excellent studies that went extremely deep into the epigenomes of just a handful of cell lines. However, a broad analysis of DNA methylation across many different cell types has been missing. This is what we address with the DNA methylation fingerprint paper”.
According to Esteller, “Among the cancer part, it shows that every tumor type has its own profile of aberrant DNA methylation (with independence of the normal tissue-type specific methylation), that the aberrations in DNA methylation increase with the degree of tumorigenesis, that DNA methylation profiles in the primary tumor can predict the site of further dissemination and that the obtains fingerprints are useful to right classify the cancers of unknown primary (this is an important clinical issue)”. Therefore, the study‘s results also provide proof-of-principle that the obtained DNA methylation fingerprints might be useful for translational purposes by helping to identify the tumor type origin of cancers of unknown primary. It is thought that the classification of cancers of unknown primary could become valuable for clinical diagnostics if validated by additional studies.
Bock concluded: “This study underlines the scientific value of large-scale reference epigenome projects such as the NIH Roadmap Epigenome Initiative (focusing on stem cells and somatic cell types of multiple lineages) and the new BLUEPRINT European epigenome mapping consortium (focusing on hematopoietic cells and diseases). The study was conducted as part of the EU-FP7 CANCERDIP project”.
Source: Fernandez AF, Assenov Y, Martin-Subero J et al. A DNA methylation fingerprint of 1628 human samples. Genome Res. doi: 10.1101/gr.119867.110. (2011) (Epub ahead of print).
Whether or not the effects of stress can be transmitted through the generations without changes to the DNA sequence has been a point of controversy among researchers since the actual mechanism(s) controlling it is unknown. However, researchers at the RIKEN Tsukuba Institute in Japan have recently published findings in the journal, Cell, that hope to shed light on this phenomenon.
Dr Shunsuke Ishii, lead author of the study explained to Epigenomics that “The key factor of our present finding is a transcription factor ATF-2, which belongs to the ATF/CREB family containing the B-ZIP type DNA-binding domain. Almost 20 years ago, we first identified ATF-2 by cDNA cloning, and since then my group has been working on ATF-2”. The researchers carried out their experiments on Drosophila, where they identified that ATF-2 is required for heterochromatin assembly in multicellular organisms. When they exposed the Drosophila to stressful conditions, ATF-2 was modified and caused disruption to the heterochromatin, unsilencing related genes. Notably, it is these epigenetic changes that can ultimately be passed down from one generation to the next.
Ishii commented on the significance of their study: “Our study has great impact, because there has been a lot of discussion as to whether the stress effect can be transmitted to next generation without DNA sequence change. Many people were doubtful about the existance of such phenomena, because the mechanism is unknown. Our finding of the mechanism has now demonstrated that such phenomena can occur”. Explaining the wider implications of the findings, Ishii mentioned that “All species from yeast to human have ATF-2, which have similar characteristics. ATF-2 is activated under various stresses, including environmental stress, metabolic stress, psychological stress and pathogen infection stress. Therefore, we think that the epigenome change caused by those stresses via the ATF-2 family of transcription factors might be inherited. Actually, we previously reported that social isolation stress on mice can induce serotonin receptor 5b gene, which leads to a depression-like abnormal behavior, via phosphorylation of ATF-7, the ATF-2 related factor. We now speculate that various diseases (e.g., lifestyle-related diseases such as heart diseases and diabetes as well as psychological disorders such as schizophrenia) could be correlated with the stress-induced epigenetic change”.
When asked what the next steps are for Dr Ishii and his research team, Ishii explained that the following questions would first need to be answered by conducting more experiments with flies, mice and humans: “Which genes are regulated by ATF-2 in response to stress? What kinds of stress modulate the specific target genes via ATF-2 family of transcription factors? Whether the stress-induced change of expression of specific target genes is really inherited? If the answer to the last question is ‘yes‘, then we would need to clarify the relationship between the change of gene expression inherited and the specific disease”.
Source: Seong KH, Li D, Shimizu H, Nakamura R, Ishii S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell 145(7), 1049–1061 (2011).
Data obtained from a Phase III study (RTOG 0525) of the drug temozolomide and its use in glioblastoma (GBM) patients has shown favorable results for using MDxHealth‘s (Belgium) companion diagnostic test called the ‘Predict MDx™ for Brain‘ (MGMT test) in conjunction with the drug to help personalize brain cancer treatment. These results of the study were presented at the Annual Meeting of the American Society for Clinical Oncology which was held in Chicago, USA between the 3 and 7 of June 2011. The investigators aim was to assess whether a continuous dose of temozolomide would be more effective than standard therapy. The MGMT test was used in this study to determine MGMT gene methylation status and molecular risk classification in patients.
Commenting on the study, Dr Jan Groen, CEO of MDxHealth explained to Epigenomics, “Although the dose-dense temozolomide regimen was not shown to improve the progression-free or overall survival, the key finding for MDxHealth‘s PredictMDx MGMT test was that methylated patients have a longer progression-free and longer overall survival versus unmethylated patients, regardless of the dosing regimen. Thus, the study confirmed that the MDxHealth PredictMDx MGMT assay properly identifies GBM patients who are more likely to respond to chemotherapeutic regimens that include temozolomide”.
The MDxHealth Predict MDx MGMT test measures the methylation status of the DNA repair gene MGMT. The test is based on real-time methylation specific PCR (MSP) technology and allows for the quantitation of dense methylation of the MGMT gene.
“Accurately identifying patients as MGMT methylated by the MSP technique allows for the stratification of patients for clinical studies in GBM, since any new investigational compound or technique will be compared with the standard of care. In addition, these new compounds are often added to the current standard of care, thus the knowledge of who is most likely to have an extended time to progression or extended survival time is key to understanding the efficacy of the investigational compound”, concluded Groen.
Currently, this assay is being used as a companion diagnostic for several investigational compounds from different pharmaceutical companies. One of these compounds is cilengitide from Merck-Serono. In the Phase III clinical study, which just recently completed enrollment, the MDxHealth Predict MDx MGMT assay was used to select only methylated patients to receive cilingitide added to the standard of care. The assay is also a key part of multiple Phase II and Phase III clinical trials in primary GBM conducted by companies such as Merck KGaA, Roche and Merck & Co.
Source: MDxHealth Press Release: www.mdxhealth.com/news-and-events/press-releases-and-events?detail=1521090
Previous research has suggested that there could be a link between the intake of folate and the prevention of colorectal tumorigenesis, and that this link appears to be dependent of timing of the folate intake. Therefore, the aim of a study carried out by investigators at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University, Boston, MA, USA, set out to elucidate the effect of altering folate (and related B vitamin) availability during in utero development in naturally occurring mouse models of colorectal cancer. The results of this interesting study were published online on 9 June 2011, in the journal, Gut.
For the mouse experiments, the mothers were fed diets containing supplemental, adequate or mildly deficient quantities of vitamins B2, B6, B12 and folate prior to conception until weaning after which all of the offspring received the same adequate diet.
Speaking to Epigenomics, Dr Jimmy Crott, lead author and a scientist at the Vitamins and Carcinogenesis Laboratory at the USDA HNRCA, explained: “Its known that various maternal exposures may result in pathologies that present at birth or in the early years of life but this is really one of the earliest pieces of evidence indicating that a mothers diet may also influence the risk of a disease that normally presents in the later decades of life”.
The investigators associated the tumor suppression observed in the offspring of supplemented mothers with a protection against disruptions to the Wnt signaling pathway, which are commonly altered in colorectal cancer.
Although it remains unknown whether maternal consumption of folate could impact colorectal tumor development in humans, Crott explained that “Because the concept of maternal transmission of disease risk is still rather novel, and evidence for cancers that appear later in life was essentially nonexistent, there has been some resistance and doubt amongst our peers. Luckily, we persisted and now we have some really interesting data that we plan to build upon over the coming years”.
Crott concluded that “These data indicate that maternal B vitamin supplementation may not only protect offspring against birth defects but also against colorectal cancer in adulthood. We next plan to gain a better understanding of the mechanisms involved and are currently funded to determine whether paternal diet may similarly impact on tumorigenesis in offspring”.
Source: Ciappio ED, Liu Z, Brooks RS, Mason JB, Bronson RT, Crott JW. Maternal B vitamin supplementation from preconception through weaning suppresses intestinal tumorigenesis in Apc1638N mouse offspring. Gut 2011.240291 (2011) (Epub ahead of print).