Scientists from Emory University (GA, USA) have reported, in the first study of its kind, age-related DNA methylation changes in pediatric blood samples. Much research has described the patterns of DNA methylation that take place in adulthood, as well as the DNA methylation plasticity that takes place during embryogenesis. However, little has been documented concerning these changes in childhood, with many studies reporting that little or no methylation takes place in pediatrics: monozygotic twins have been observed to show indistinguishable methylation. Despite this, new research claims that methylation of the DNA in blood cells takes place more rapidly in infants.
By examining the methylation patterns of 27,528 CpG dinucleotides in DNA from the blood of 398 boys aged 3–17 years the investigators found age-related changes in 2078 nuclei. Reid Alisch, lead author of the paper, spoke to Epigenomics about the significance of this study: “This work is the first to look comprehensively at a large group of pediatric boys to determine whether DNA methylation is changing during childhood. Our study finds that the majority of loci previously found to be changing in adults are also changing in children; however, we also find that the loci are changing three- to five-times faster in children than adults, providing an explanation to why we find so many more loci in the pediatric populations.”
Of particular interest, the researchers found a deficit of age-related changes on the X chromosome, demethylation events have a preference for specific nucleotides surrounding the CpG dinucleotide, and that many of the affected loci were associated with the developmental and immune systems. The authors proposed that the lack of age-related changes occurring on the X chromosome may be due to the subjects being male and their X chromosome less tolerant of methylation variations. Alisch went on to explain, “we find evidence to suggest that these changes are systematic rather than stochastic and that they are associated with biologically relevant childhood ontological functions.”
The findings of this study may have important implications on future epigenetic research, as emphasized by Alisch, who commented, “our data indicate that it is imperative to account for age in disease-based DNA methylation studies and that traditional linear statistical approaches are not sufficient to account for the age-effect.” It seems clear that further research is required to improve understanding of pediatric methylation patterns and Alisch had several suggestions as to what directions should be taken: “In the future, a longitudinal study is needed to study the lifetime effect within the individual. It will also be of interest to determine if childhood disease effects the rate of age-associated DNA methylation changes.”
Source: Alisch RS, Barwick BG, Chopra P et al. Age-associated DNA methylation in pediatric populations. Genome Res. doi:10.1101/gr.125187.111 (2012) (Epub ahead of print).
New research from scientists at Maastricht University (Maastricht, The Netherlands) has shed light on some of the epigenetic effects of assisted reproduction treatment (ART), highlighting some of the potential drawbacks of this technology. It has been noted in recent years that offspring who are conceived with the aid of ART are at an increased risk for developing Beckwith–Wiedmann Syndrome (BWS). In addition to this, the number of cases being reported for children conceived by methods such as in vitro fertilization are rising. BWS is an imprinting disorder characterized by overgrowth, usually present at birth. It has been proposed that using ART poses an epigenetic risk, prompting researchers to try and uncover what changes may be taking place.
The group, led by Peter de Boer, performed a literature search in an attempt to ascertain what links may exist between ART and epigenetic effects in both humans and mice. Specifically, they looked for data on transgenerational epigenetic inheritance and epigenetic effects induced by ART.
After analyzing the gathered data, they found that at the level of genomic imprinting involving CpG methylation, ART-induced epigenetic defects are observed frequently in mice, with the placenta appearing more vulnerable than the embryo. Ovulation induction and in vitro culture also had clear effects on imprinting. In humans, sequence-specific hypomethylation has been observed in sperm from compromised spermatogenesis. It may also be likely that ART could cause imprinting differences in genes involved in metabolism, leading to low-weight births and various chronic diseases. The researchers also noted the possibility that fertility deficiencies themselves could have an effect on imprinting.
The data appear to support the notion that ART may have a detrimental effect on the epigenetics of offspring, leading to developmental disorders such as BWS. The group did note however that the effects seems to be more apparent in mice than humans, commenting that: “In the human, indications for a broader target for changes in CpG methylation than imprinted DNA sequences alone have been found.” However, the authors feel that further work will unravel this relationship, commenting “the definite answer to many questions in both the mouse and human will await genome-wide epigenetic profiling in the different variants of ART. From the patient‘s perspective, those that contribute sperm from poor spermatogenesis stand out as very interesting for such an analysis as do the oocytes from older women.”
Source: van Montfoort AP, Hanssen LL, de Sutter P, Viville S, Geraedts JP, de Boer P. Assisted reproduction treatment and epigenetic inheritance. Hum. Reprod. Update 18(2), 171–197 (2012).
New evidence has emerged to support the theory that sulforaphane (SFN) could be an effective compound for preventing the development of cancer, and it may achieve this through epigenetic mechanisms. A research group from Oregon State University (OR, USA) believe that SFN may be able to act as a chemopreventative agent in prostate cancer by epigenetically modulating genes involved in the regulation of the cell cycle.
SFN, an isothiocyanate derived from cruciferous vegetables, is a known inhibitor of histone deacetylase enzymes. However, the authors chose to investigate what effects SFN may have on DNA methylation, an area currently understudied in cancer epigenetics. Hypermethylation of cyclin 2, a gene that regulates the cell cycle, is known to correlate with the progression of prostate cancer, characterized by higher Gleason scores and aggressive forms of tumors. However, prevention of this methylation has been demonstrated to have antiproliferative effects in prostate cancer cells.
The researchers, who published their study in Clinical Epigenetics, examined the global methylation status and the methylation status of CpG islands in the promoter region of cyclin D2 in LnCap cells of the prostate. They found that SFN significantly decreased the expression of a number of DNA methyltransferases, especially DNMT1 and DNMT3b. Of particular interest was the finding that SFN significantly decreased methylation in cyclin D2 promoter regions containing c-Myc and Sp1 binding sites. This decreased methylation resulted in an increase in cyclin D2 transcript levels, leading the authors to propose that perhaps SFN alleviates methylation-induced silencing of this gene.
Although this study focused on prostate cancer cell, these processes are likely to have a role in many other forms of cancer, such as in the breast and colon, where cyclin D2 is thought to play a similar role in carcinogenesis. Expanding on pervious research that has linked SFN with the inhibition of histone deacetylases, the authors think that both of these mechanisms may be epigenetically modulated in cancer, and that the crosstalk between these processes is affected. The role of SFN as a chemopreventative agent in certain forms of cancer means that there is potential for it to be developed into a treatment method in the future. However, in their discussion, the authors emphasize that more work needs to be done to understand the molecular changes that are taking place: “Studies that identify specific methyl-binding proteins, transcriptional activators or repressors and chromatin remodeling will be essential to decipher the exact mechanism of cyclin D2 promoter regulation by SFN.”
Source: Hsu A, Wong CP, Yu Z, Williams DE, Dashwood RH, Ho E. Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells. Clin. Epigenetics doi:10.1186/1868–7083–3–3 (2012) (Epub ahead of print).
A new platform to house and view Human Epigenomic Atlas data has been unveiled by Washington University (MO, USA). This new tool has been produced as a part of the Roadmap Epigenomics Project, a consortium aiming to produce a public resource of human epigenomic data to aid researchers in basic biological and disease-focused research.
The Human Epigenome Browser from Washington University, maintained by the Epigenome Informatics Group, boasts a system containing over 8000 epigenome datasets obtained from the Human Epigenome Atlas and the Encyclopedia of DNA elements, covering over 100 cell and tissue types. Information particularly useful to researchers in the field of epigenetics includes data on DNA methylomes, histone marks, open chromatin and RNA splicing profiles.
The team behind this new resource, including Tim Wang and Xin Zhou, have included full instructions and tutorials on the browser‘s website, as well as video tutorials and example datasets to aid users in becoming familiar with the program. The creators believe the browser has the potential to be a useful tool for researchers, commenting on the website that “its use of advanced, mutliresolution data formats and its userfriendly interface make it possible for investigators to upload and visualize their own data as custom tracks.”
Sources: Washington University School of Medicine: http://epigenomegateway.wustl.edu; Epigenie: www.epigenie.com/Headlines/Human-Epigenome-Browser-Washington-University.html
– All stories written by Jonathan Wilkinson