“We started out studying a basic scientific question, namely what was the noncoding RNA doing, simply to satisfy our scientific curiosity. In the process, we discovered the novel finding that RNA inhibits methylation and experimentally we can introduce RNAs to ‘switch on‘ tumor suppressors, which have been shut off,” comments Daniel Tenen, leader of the investigators from the Cancer Science Institute of Singapore (National University of Singapore, Singapore). “Our results suggest strategies for gene-selective demethylation of therapeutic targets in human diseases such as cancer.”
The scientists from the National University of Singapore, and the Harvard Stem Cell Institute (MA, USA), identified new noncoding RNA that may be able to ‘switch on‘ previously silent tumor suppressor genes in cancer cells that could inhibit tumor formation. The study, published in Nature, reports novel RNA that is critical for regulating DNA methylation and is associated with silencing gene expression in many diseases.
The authors focused on noncoding RNA for the tumor suppressor CEBPA, the silencing of which is associated with various types of cancer including lung cancer and acute myeloid leukemia. The RNA studied was found to bind to a DNA methylation enzyme, leading to the prevention of methylation at the CEBPA suppressor; therefore, the gene was not silenced and the suppressor could have an active effect with in the cell.
The study concludes that this principle could be widened to potentially ‘switch on‘ tumor suppressors across thousands of genes. The researchers will continue to examine the role of RNA in regulating other epigenetic factors, alongside investigation into the development of tools to target activation of more tumor suppressors.
Source: National University of Singapore press release: http://news.nus.edu.sg/highlights/6867-csi-singapore-finds-new-way-to-switch-on-silenced-tumour-suppressors
Recent evidence, presented at the 26th European College of Neuropsychopharmacology Congress (Barcelona, Spain) in October, demonstrates a link between epigenetic regulation and Alzheimer‘s disease (AD). These findings are proposed to help lead the way to new early diagnostic methods and novel treatment options for common dementias.
Daniel van den Hove (Maastrict University, Maastricht, The Netherlands) who presented the research speculates: “Because epigenetic processes are known to be dynamic and reversible, future treatment strategies directly targeting epigenetic regulation may provide powerful means for pharmacological and/or behavioral intervention strategies in neurodegenerative disorders like AD.”
The researchers aimed to investigate epigenetic mechanisms and their role in both AD and aging in mice and men. In mice, histone deacetylase 2 (HDAC2) was shown to increase with age. This is involved in the methyl-CpG-binding complex and is important for memory formation and neurodegeneration-related cognitive impairment. It was also found that increased hippocampal DNA methyltransferase 3a was associated with aging. This novel DNA methyltransferase has been shown to be important in cell differentiation and proliferation. Furthermore, 5-hydroxymethylcytosine and 5-methylcytosine were also identified, which are markers for DNA hydromethylation and methylation, respectively.
The researchers from Maastricht University also collaborated with investigators from the Banner Sun Health Research Institute (AZ, USA) to perform studies on human brain tissue. They demonstrated that different hydroxymethylation and methylation patterns were identified in AD pathology compared with those seen in normal aging.
“We have found robust decrements of 5-methylcytosine and 5-hydroxymethylcytosine in the hippocampus of AD patients when compared with carefully matched controls. Interestingly, this decrease correlated with hippocampal amyloid plaque load,” explained van den Hove.
In order to investigate whether the identified changes were associated with abnormal amyloid processing, the researchers studied the same epigenetic markers in the hippocampus of a mouse model of AD. Global methylation and hydroxymethylation did increase with age in normal mice, whereas in AD mice, an age-related imbalance of DNA methylation occurred with the onset of AD pathology.
These various data demonstrate a clear link between epigenetic markers of methylation and AD pathology and it is speculated that these may lead to novel diagnostic tests and therapies in the future. However, specificity and safety require further research before epigenetic-based therapies could be clinically relevant.
Source: European College of Neuropsychopharmacology Congress press release: www.ecnp-congress.eu/~/media/Press%20release%20Epigentic%20markers%20in%20Alzheimers%20disease%20ECNP%202013.pdf
Scientists from Queen Mary University of London (London, UK) have identified possible epigenetic markers to aid in the prediction of head and neck cancer. Published in Cancer, this research holds the potential to assist the development of noninvasive tests, which could be clinically utilized in the future.
Researchers analyzed 93 malignant tissue samples from cancer patients from the UK and Norway, and compared these with either noncancerous tissue from the same patients or donated tissue from healthy individuals undergoing wisdom tooth extraction. The aim of the investigation was to identify whether epigenetic changes in cancerous tissues were seen in healthy cells, as it is already known that abnormal DNA methylation precedes cancer development.
Eight FOXM1-induced differentially methylated genes were investigated, two of which (GLT8D1 and C6orf136) were identified to be differentially expressed in squamous cell carcinomas of the head and neck. The researchers then confirmed, using methylation-specific quantitative PCR, that the promoter regions for GLT8D1 and C6orf136 were hypo- and hyper-methylated, respectively.
Epigenetic modifications precede gene expression; therefore, the methylation status of candidate genes, such as those identified in the present study, may act as predictive markers in the future.
“These epigenetic markers could be clinically exploited as biomarkers for early pre-cancer screening of head and neck cancer. However, further work is needed, as we are purely at the discovery stage at the moment and have not used this as a diagnostic test as yet. The eventual aim would be to test asymptomatic patients and/or people with unknown mouth lesions. An advantage of epigenetic DNA markers is that it may be possible to measure them using noninvasive specimens. So it could enable the use of saliva, buccal scrapes or blood serum for early cancer screening, diagnosis and prognosis,” commented lead research Muy Tach-Teh, from the Institute of Dentistry at Queen Mary University.
Sources: Hwang S, Mahadevan S, Qadir F et al. Identification of FOXM1-induced epigenetic markers for head and neck squamous cell carcinomas. Cancer doi:10.1002/cncr.28354 (2013) (Epub ahead of print); Queen Mary University of London press release: www.qmul.ac.uk/media/news/items/smd/115025.html
A study published in Epigenetics has described vital differences between T- and B-lymphocyte cells purified from whole blood. These data have identified the unique epigenetic profile of these healthy immune cells and may lead to further investigation of DNA methylation processing in a variety of diseases in which these immune cells play fundamental roles.
Researchers, led by John Glossop (Keele University, UK), used Infinium HumanMethylation450 BeadChips (Illumina®, CA, USA) to conduct genome-wide DNA methylation profiling. A total of 450,000 candidate genes were included from matched pairs of T and B lymphocytes collected from ten healthy females.
The data were processed to identify differential methylation and 679 CpGs (representing 250 genes) were demonstrated to have consistent differences in each sample. The T and B lymphocytes were differentially methylated in these regions with 76.6% being hypermethylated in B lymphocytes. Furthermore, hierarchical clustering of the sample demonstrated segregation into two distinct clusters based on cell type.
This work reveals the intrinsic differences in DNA methylation present between T and B lymphocytes, unique to a specific number of related genes. In this way, these data may lead to further investigation of DNA methylation in immune cell types across a variety of diseases, where T and B lymphocytes are known to be involved.
Sources: Glossop J, Nixon NB, Emes RD et al. Epigenome-wide profiling identifies significant differences in DNA methylation between matched-pairs of T- and B-lymphocytes from healthy individuals. Epigenetics 8, 11 (2013); Keele University press release: www.keele.ac.uk/pressreleases/2013/ground-breakingfindingsbykeeleepigeneticsandrheumatologygroups.html
“Since early identification of pathological changes is crucial to enable therapeutic intervention in Parkinson‘s disease before major neurologic damage occurs, these findings could prove important in monitoring disease progression and the effectiveness of treatment,” commented Paula Desplats (UC San Diego School of Medicine, CA, USA), lead author on the study published in Epigenetics, which investigated genome-wide methylation in brain and blood samples of Parkinson‘s disease (PD) patients. The results provide evidence for an association between PD and DNA methylation that may be clinically utilized as a biomarker in the future.
This new research builds upon previous findings from UC San Diego in which a significant decrease in DNA methylation was identified in the frontal cortex of individuals affected by dementia with Lewy bodies and PD. In the current study, the researchers identified DNA methylation patterns in peripheral blood leukocytes and postmortem frontal cortex samples from five PD patients compared with that of six age-matched, healthy controls using genome-wide DNA methylation profiles.
It was demonstrated that the methylation profiles gathered from the blood samples were able to distinguish those with PD from healthy controls. The group identified 124 genes among both the blood and brain samples, which could be utilized for further biomarker investigation.
PD is a neurodegenerative disorder for which diagnosis is not usually achieved until significant motor symptoms develop, by which point substantial damage to the midbrain (specifically the substantia nigra) has occurred. The evidence from the current study highlights a role for epigenetic alterations in the molecular mechanisms of neurodegeneration and suggests a future function for epigenetic markers in PD diagnosis.
Sources: Masliah E, Dumaop W, Galasko D, Desplats P. Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 8(10), 1030–1038 (2013); University of California, San Diego Health Sciences news: http://ucsdhealthsciences.tumblr.com/post/57717074992/the-epigenetics-of-parkinsons-disease
– All stories written by Elizabeth Webb