NHLBI Working Group Epigenetic Contributions to Coronary Artery Disease

Executive Summary

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.

Discussion:

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.

Recommendations:

  • Encourage multidisciplinary research approaches to demonstrate that epigenetics contributes to cardiovascular disease using samples derived from human subjects
  • Define cardiovascular specific epigenetic code under normal and disease conditions including candidate loci as well as global patterns in:
    • Human cells and tissues
    • Animal models
    • Identification of atherogenic prone epigenetic histone code
    • Rupture prone plaque
    • Stable atherosclerotic disease
  • Determine whether the cardiovascular epigenetic code is similar across species
    • How stable/dynamic are histone modification patterns? What are the functional differences between different patterns?
    • Do different tissues/organs exhibit different modification patterns?
  • Support studies investigating molecular mechanisms that affect the epigenetic code
    • Stimulate the development of inhibitors/activators of key chromatin marks
    • Enable correlation of epigenetic marks with CVD and obesity
    • Compare epigenetic marks with genetic marks and correlate with disease severity
  • Support development of sensitive and high throughput assays and technologies for determining the cardiovascular epigenome
  • Initiate efforts to map epigenetic markers in cardiovascular tissues from mice susceptible or resistant to complex diseases such as atherosclerosis
  • Define mechanisms that control epigenetic programming in embryonic and adult stem cells, for example, the maintenance of pluripotency versus differentiation
  • Promote research projects that use experimental design to prove, or at least provide evidence for causation
    • Longitudinal, studies
    • Animal models
    • Hybrid designs
  • Establish whether circulating blood cells accurately reflect systemic and/or specific target organ histone modification patterns
  • Support the development of improved bioinformatics and statistical methods for further mining of genome-wide epigenetic databases
  • Initiate development of experimental approaches to test how locus selective manipulation of epigenetic marks alters gene expression (i.e. are changes cause or an effect?)

References:

  1. Nature 447, 396-398 (24 May 2007)

Publication Plans:

The workshop/working group meeting summary is planned for publication in a peer-reviewed journal.

NHLBI Contact:

Pothur Srinivas, Ph.D., MPH., NHLBI, NIH
srinivap@nhlbi.nih.gov

Phyliss Sholinsky, MSPH, NHLBI, NIH
sholinsp@nhlbi.nih.gov

Dina Paltoo, Ph.D., MPH., NHLBI, NIH
paltood@nhlbi.nih.gov

Working Group Members:

Chair: Gary K. Owens, Ph.D., University of Virginia

Members:

  • Stanley Hazen, M.D., Cleveland Clinic Lerner College of Medicine
  • Da-Zhi Wang.  Ph.D., University of North Carolina
  • Keji Zhou, Ph.D., National Heart, Lung, and Blood Institute
  • Nilamadhab Mishra, M.D., Wake Forest University
  • Rama Natarajan, Ph.D., Beckman Research Institute of the City of Hope
  • Jan Bressler, Ph.D., MPH, University of Texas Health Science Center
  • Andres Houseman, Ph.D., Harvard School of Public Health

Last updated: December 5, 2008

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