Researchers from Boston University School of Medicine (MA, USA) have identified a way to affect cell signaling that may prevent angiogenesis, the formation of new blood vessels, and therefore cancer growth. The research, published in Science Signaling, demonstrated that by interfering with the epigenetic regulation of a VEGF receptor, tumor growth could be blocked.
Angiogenesis has been implicated in multiple disease processes including age-related macular degeneration and cancer. VEGF receptor 2 (VEGFR-2) is located on the surface of blood vessels and known to be involved in angiogenesis in damaged cells, when VEGF is produced. VEGF, as a signaling protein, binds to VEGFR-2 and can activate biochemical mechanisms inside blood vessels to trigger angiogenesis. Various US FDA-approved drugs affect this process yet often exhibit limited efficacy, and patients can develop drug resistance.
The present research, led by Nader Rahimi (Boston University School of Medicine), reported that by altering methylation, one function of which is to regulate gene expression, it is possible to effectively interfere with VEGFR-2-mediated angiogenesis. By pharmacologically inhibiting methylation of a Lys residue (Lys[1041]) on VEGFR-2, the investigators demonstrated they were able to block angiogenesis in zebrafish and tumor growth in mice.
The study concludes that Lys(1041) methylation is important for post-translational modifications, and this epigenetic approach could be a novel target for future cancer drug development. “The study points to the methylation of VEGFR-2 as an exciting, yet unexplored drug target for cancer and ocular angiogenesis, ushering in a new paradigm in antiangiogenesis therapy,” concluded Rahimi.
–Written by Elizabeth Webb
Sources: Boston University School of Medicine press release: …www.bu.edu/news/2013/12/04/methylation-signaling-controls-angiogenesis-a…; Hartsough EJ, Meyer RD, Chitalia V et al. Lysine Methylation Promotes VEGFR-2 Activation and Angiogenesis. Sci Signal. 6, ra104 (2013); http://epigenie.com/tet1-demethylation-wipes-the-genomic-imprinting-slate-clean/; http://www.sciencedaily.com/releases/2013/12/131209105348.htm
Research presented at the American College of Neuropsychopharmacology annual meeting in Hollywood (FL, USA) has reported evidence that advanced paternal age could be associated with the development of psychiatric disorders in offspring. Maria Milekic (Columbia University Medical Center, NY, USA), who reported the findings, has been investigating the epigenetic effects of paternal age in mice. It appears that epigenetic alterations in the expression of genes could account for the development of psychiatric diseases such as autism.
Milekic explained the rationale of the study: “We were interested in understanding the mechanism of the paternal age effect. The risk for schizophrenia increases twofold when a father is over 45 years of age, and the risk for autism increases two- to five-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism.”
The researchers tested two groups of mice, with ten breeder mice in each group. The two groups of breeders were defined as old (12-month-old) or young (3-month-old) males, each bred with young (3-month-old) mice. When the offspring were at 3 months, their behavior was tested. In addition to this, DNA methylation in the sperm of the young and old fathers was evaluated, as well as in the brains of the offspring. The gene expression of the offspring was also tested.
It was found that the offspring of old fathers showed the same deficit in DNA methylation; in addition, their behavior was also markedly different from their young counterparts. In particular, they demonstrated reduced exploratory activity and differed in the startle response, as well as in habituation. Further to this, the offspring of the old fathers also showed differences in the expression of genes that have been implicated in autism spectrum disorders and brain development, when compared with the offspring of young fathers.
This study highlights the importance that epigenetics, and DNA methylation in particular, could have in the development of psychiatric disorders such as autism and schizophrenia. By studying these effects further, possible therapeutic interventions could be identified. Milekic described what direction their research will take in furthering their understanding of epigenetics: “We are trying to evaluate changes in different brain regions. Our studies before did not compare brain regions. Most of the genes that have altered expression are in the cerebellum. We are interested in how DNA methylation in the cerebellum is affected by paternal age.”
–Written by Jonathan Wilkinson
Source: American College of Neuropsychopharmacology press release, via EurekaAlert!: http://www.eurekalert.org/pub_releases/2013-12/acon-aag120813.php
A study published in Human Molecular Genetics has examined the gene changes observed in smokers and users of smokeless tobacco.
The genome-wide DNA methylation study, carried out by researchers from Uppsala University (Sweden), aimed to determine the effects of smoke and snuff (smokeless tobacco) on DNA methylation. A total of 95 sites were observed to be differentially methylated in smokers and a subset of the differentially methylated loci were also found the be differentially expressed in smokers. No sites, biological functions or molecular processes were observed to be enriched for smokeless tobacco-related differential DNA methylation.
The researchers deduced from their findings that the methylation changes observed are caused by the burnt products of tobacco, rather than its basic components. Genes involved in response to arsenic were observed to be enriched, correlating with the knowledge that the smoke contains small amounts of arsenic. A number of molecular processes and biological functions were also observed to be enriched for smoke-related DNA methylation changes, including some linked to diabetes, the immune system and male fertility.
Discussing the study, author Åsa Johansson (Uppsala Clinical Research Center, Sweden) stated: “This means that the epigenetic modifications are likely not caused by a substance in the tobacco, but by the hundreds of different elements that are formed when the tobacco is burnt. It has been previously known that smokers have an increased risk of developing diabetes and many types of cancer, and have a reduced immune defence and lower sperm quality. The results from the study also showed that genes that increase the risk for cancer and diabetes, or are important for the immune response or sperm quality, are affected by smoking.
“Our results therefore indicate that the increased disease risk associated with smoking is partly a caused by epigenetic changes. A better understanding of the molecular mechanism behind diseases and reduced body function might lead to improved drugs and therapies in the future,” summarized Johansson.
–Written by Hannah Wilson
Sources: Besingi W, Johansson A. Smoke related DNA methylation changes in the etiology of human disease Hum. Mol. Genet. doi:10.1093/hmg/ddt621 (2013) (Epub ahead of print); Uppsala University press release www.uu.se/en/media/news/article/?id=3111&area=2,10,16&typ=artikel&na=&lang=en
The BET family of proteins, also known as epigenetic reader proteins, recognize epigenetic changes to histone proteins and generate downstream signals for a variety of reasons, for example for cell division. While DNA stores information as genes, which are heritable through cell division, epigenetic features are inherited without being part of the genetic code. In leukemia, epigenetic changes occur that lead to dysfunctional signal transduction by way of the BET family, causing unchecked cell division and ultimately damage throughout the organism.
A new agent (XD14) has been found to suppress the high level of unchecked cell division found in leukemic cells by suppressing the activity of BET family proteins. This discovery comes from a research project lead by Stefan Günther (University of Freiburg, Germany), but also included research groups from SFB 992 Medical Epigenetics headed by Manfred Jung (Institute of Pharmaceutical Sciences, University of Freiburg), Oliver Einsle (Institute of Biochemistry, University of Freiburg) and Roland Schüle (Freiburg University Medical Center).
Virtual screening was used to identify XD14, with approximately 10 million molecules initially being screened as having a binding affinity strong enough to prevent signal transduction by BET family proteins. bwGRID, a computer network maintained by the Baden-Württemberg universities (Germany), was used to carry out the complex calculations. XD14 was tested on 60 different types of cancer and found to successfully and significantly suppress unchecked cell division in leukemia cells. The transition of this agent to a usable drug is now being investigated.
Combating diseases through targeting epigenetic mechanisms is currently a popular research area, with approximately 20 research groups from the University of Freiburg, the Freiburg University Medical Center and the Max Planck Institute of Immunobiology and Epigenetics (Freiburg, Germany) working together to study this area. In the future, it is expected that many more agents like XD14 will be identified.
–Written by Aradhana Gohil
Sources: Lucas X, Wohlwend D, Hügle M et al. 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew. Chem. Int. Ed. Engl. DOI:10.1002/anie.201307652 (2013) (Epub ahead of print); University of Freiburg press release: http://www.pr.uni-freiburg.de/pm/2013/pm.2013-11-26.328-en