Both acute and repeated cocaine administration found to significantly alter the expression of H3K9me3 and the typically silenced LINE-1 like repetitive elements in the nucleus accumbens.
A team from the Fishberg Department of Neuroscience at the Mount Sinai School of Medicine (NY, USA) have successfully generated high-resolution profiles of heterochromatic regions in the reward region of the brain, and determined how these chromatin regions are affected by exposure to cocaine. These findings serve to illustrate the importance of studying chromatin mechanisms in addiction and, in particular, the use of genome-wide methods such as chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq).
Though it has long been established that cocaine can regulate the structure of chromatin in the nucleus accumbens, research in this area has paid little attention to the effect of cocaine exposure on the transcriptionally silent regions of the adult brain.
Asked why the results of this study are so significant, Dr Nestler, Professor and Chair of Neuroscience at the School and lead researcher remarked: “The results are the first to show cocaine regulation of trimethylation of Lys9 on histone H3 (H3K9me3). In fact, this is the first study to report that this chromatin mark is subject to dynamic regulation in the adult brain”.
This extremely effective repressive mark, H3K9me3 typically dominates the silenced heterochromatic regions in the nucleus accumbens. Nestler went on to highlight the implications of this finding: “This is interesting because it shows that nerve cells regulate the total amount of heterochromatin in their nuclei; it demonstrates profound genomic effects of cocaine. It also shows that the regions of the genome subject to this regulation are nongeneric regions, thereby implicating such nongenic regions (e.g., line elements) in cocaine action”.
As well as altering chromatin remodeling activity, exposure to cocaine was also shown to alter genome-wide transcriptional regulatory networks and gene-expression profiles.
The authors believe that this mechanism might be behind some of the lasting effects of drug use and addiction. On how the results of the study should be carried forward, Dr Nestler speculated: “It would be interesting to study the functional consequences of such H3K9me3 regulation in terms of the activity of the nerve cells, their structure and the animals‘ behavioral responses to cocaine”.
Source: Maze I, Feng J, Wilkinson MB, Sun H, Shen L, Nestler EJ: Cocaine dynamically regulates heterochromatin and repetitive element unsilencing in nucleus accumbens. Proc. Natl Acad. Sci. USA 108(7), 3035–3040 (2011).
A new method for identifying recurrent combinatorial chromatin modifications across a given epigenome has been created by researchers at the University of Iowa (IA, USA). The Coherent and Shifted Bicluster Identification (CoSBI) algorithm is a welcomed and much needed addition to a field which is currently lacking tools for the integrative analysis of multiple chromatin modification maps.
The creation of the subspace clustering algorithm aimed to fill a knowledge gap as Dr Kai Tan, Principle Investigator and Assistant Professor of Biomedical Engineering and Internal Medicine at the University of Iowa, explains: “Recent experimental and computational studies have revealed various histone codes for functional DNA elements, including promoters and enhancers. However, the current main stream analytical tools that enabled the discoveries only look at one or two chromatin modification maps at a time”.
Indeed, for the majority of studies, data integration exists as a post-processing step. Dr Tan, who is also a Professor of Applied Mathematical and Computational Sciences at the university, attributed the team‘s motivation for developing the new tool to needing a better understanding of the complexity of chromatin modifications: “The field of epigenetics really lacks tools for integrative analysis of multiple chromatin modification maps as well as integration with other data types”.
The algorithm was tested on a set of 39 chromatin modification maps derived from human T cells and discovered a total of 843 different combinatorial patterns present in over 0.1% of the genome. In addition, combinatorial signatures for eight classes of functional DNA elements were found.
On possible future applications of the tool, Dr Tan speculates: “Application of our tool to the human T-cell data has already generated many testable hypotheses. For instance, we find novel chromatin modifications and their combinations associated with promoters and enhancers. These could be the first things that we would like to test. In addition, as several large-scale epigenome mapping projects are in full swing, application of our tool will aid data interpretation and generation of novel insights into epigenetic mechanisms of gene regulation”.
CoSBI is freely available for academic researchers and the Iowa team are looking for collaborators to test their findings and to use the tool to study other cell types and conditions. Tan concludes: “I think that advances in this field require better computational approaches and more and better experiments and the synergy between the two approaches”.
Source: Ucar D, Hu Q, Tan K: Combinatorial chromatin modification patterns in the human genome revealed by subspace clustering. Nucleic Acids Res. (2011) (Epub ahead of print).
A new study has unexpectedly demonstrated that both the enzyme–protein level and the recruitment of the catalyzing enzymes are controlled by a epigenetic mark that is of the same level as the enzyme protein, this is dictated by the level of the product. This unexpected self-regulatory inheritance mechanism has a critical role in preserving gene-expression patterns and cellular identity.
Dr Peter Jones, Director of the USC Norris Comprehensive Cancer Center and Distinguished Professor of Urology and Biochemistry and Molecular Biology at the Keck School of Medicine of the University of Southern California (CA, USA), comments on these findings: “This is most unusual because, normally, when the level of an enzyme‘s product goes down the enzyme goes up to try and make more product”.
Dr Jones, also a H Leslie Hoffman and Elaine S Hoffman Chair in Cancer Research, goes on to attribute this discovery to “a homeostatic mechanism that keeps the level of methylation constant and avoids spurious de novo methylation. This mechanism may well be common to other epigenetic enzymes. Many people also do not realize that the so called ‘de novo‘ enzymes play a key role in maintenance”.
Asked how the results of the study may be carried forward, the Keck Professor highlights: “Many investigators do not realize that all of the DNMT3a and 3b inhibitors are firmly anchored to the nucleosomes containing methylated DNA, that is the enzyme stays with its product and is stabilized by it. There is no free enzyme in the cell, and hence, studies looking at ‘recruitment‘ of DNMT3 to various regions need to take this into account because there is no ‘free‘ enzyme to recruit”.
As a final remark, Jones added: “Homeostasis of epigenetic marks is a key function of these processes in somatic cells – when they go wrong they can lead to disease”.
Source: Sharma S, De Carvalho DD, Jeong S, Jones PA, Liang G: Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance. PLoS Genet. (2011) (Epub ahead of print).
This comprehensive study was performed by researchers in the laboratory of Dr Trygve Tollefsbol at the University of Alabama at Birmingham (AL, USA) and entailed the study of various bioactive dietary supplements and their epigenetic targets in many types of cancer. The findings are published in the journal Clinical Epigenetics.
Commenting on the rationale behind conducting the study, Dr Syed Meeran, current Tollefsbol laboratory postdoctoral fellow remarked: “Cancer is a multistep process and uses many survival pathways to prevail over normal cells. Therefore, bioactive components which have numerous molecular targets and suppress multiple cellular pathways may have strong potential for cancer prevention and treatment”.
The Birmingham research associate went on to discuss the importance of these compounds, highlighting their cost–effectiveness, wide availability and the fact that they are “not a medicine”. Their wide molecular epigenetic targets were found to range from the DNA methyltransferase DNMT1, various histone acetyltransferases and the HDAC SIRT1. An interesting finding was that grapes, which contain resveratrol, a polyphenol known for its apparent anti-aging effects in animal models, inhibit DNMTs and activate the HDAC SIRT1.
By collecting evidence for a wide range of bioactive dietary compounds and their epigenetic targets in cancer prevention and therapy, this study will be of interest to many groups of scientists, especially in the broad fields of epigenetics, cancer prevention, nutrition and clinical oncology. However, as Dr Meeran points out, it is not just the medical community that is set to benefit from the study: “This study is also helpful … to understand the importance of taking bioactive dietary compounds and the quantity of intake per day.
Asked how the results of the study should be carried forward, Dr Meeran states: “As mentioned in our article, it is clear that bioactive dietary components hold great potential … by altering various epigenetic modifications. Although individual bioactive components have shown great potential in prevention and treatment of various cancers, the combined use of dietary components should be more efficient in targeting the many cellular processes involved in tumorigenesis. Additional clinical studies should be directed to analyze the safety profile of doses, route of administration, organ specificity and bioavailability of these bioactive components in human subjects. Furthermore, synthetic compounds can be made on the basis of these bioactive dietary compounds to enhance the stability and bioavailability at physiological conditions”.
Source: Meeran SM, Ahmed A, Tollefsbol TO: Epigenetic targets of bioactive dietary components for cancer prevention and therapy.Clin. Epigenet. 1(3–4), 101–116 (2010).