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Epigenetic Contributions to Coronary Artery Disease
The National Heart, Lung, and Blood Institute convened a Working Group of expert scientists on September 4-5, 2008, in Bethesda, Maryland, to evaluate the current state of knowledge on the role of epigenetic reprogramming, including post-transcriptional modifications, contributing to coronary artery disease outcomes such as the rupture of a vulnerable plaque. Recent studies suggest that epigenetic post-transcriptional and translational modifications might play important roles in cardiovascular phenotypic modulation and disease.
The group focused on such issues as the use of epigenetic posttranslational modification and marks for detection, prevention and risk assessment of cardiovascular disease. Also discussed was the impact of epigenetic modifications on the molecular mechanisms regulating early disease development and potential use of epigenetic marks and post-translational protein modification to develop new surrogate markers for monitoring therapy and interventions.
The Working Group discussed epigenetics in the context of rupture-prone atherosclerotic plaque and the cardiovascular disease area in general. In addition to considering Adrian Bird’s recent definition of epigenetics, “the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states” the group also decided to consider processes whose mechanistic relationship with classical epigenetic mechanisms can be clearly delineated. This includes microRNAs that impact DNA methylation or histone modification.
Discussions included the availability and requirement of sample collections that have extensive phenotypic information with the expressed intention of leveraging existing resources. There was general agreement on the need for relevant animal models, understanding the stable epigenome, profiling histone methylation patterns and understanding their relationship to pathology. There was also an emphasis on understanding whether circulating cells register and reflect local events. Tissue specificity and the stability of epigenetic marks were also discussed, as well as the need for targeted and locus specific approaches to detection. Apprehending upstream mechanisms controlling epigenetic programming in cells as well as those responsible for the recruitment of histone modifying enzymes to selective gene loci were thought to be important issues in need of clarification. There was also an emphasis on deciphering the histone code as it relates to the control of vascular cells during development and its alteration in adult life. Assay platforms and the need for improved sensitivity of current assays were discussed as were requirements for performing genome-wide epigenetic profiling on small amounts of tissue, histone modification patterns and gene expression. There was also dialogue regarding the need for direct testing to determine whether epigenetic changes are a cause or consequence of changes in gene expression. Deliberations also focused on global and locus specific methylation and their correlation to functional readout. Additional discussion topics included the role of microRNA and the association between methylation classes and environmental exposure. Finally, novel and improved data analysis and study design related specifically to epigenetics were considered important and ongoing needs. The extensive discussions led to the following recommendations.
The workshop/working group meeting summary is planned for publication in a peer-reviewed journal.
Pothur Srinivas, Ph.D., MPH., NHLBI, NIH
Phyliss Sholinsky, MSPH, NHLBI, NIH
Dina Paltoo, Ph.D., MPH., NHLBI, NIH
Working Group Members:
Chair: Gary K. Owens, Ph.D., University of Virginia
Last updated: December 5, 2008