For personalized genomic medicine to be a reality, two things must happen: First, we need to directly establish the role of genetic variation in disease incidence and progression, rather than studying genetic associations and molecular mechanisms in isolation from each other. Second, we must investigate the networks of biological molecules responsible for complex diseases like cardiovascular disease as emergent molecular phenotypes, while at the same time using targeted strategies to establish causal relationships. Together, these innovations can lead to an understanding of how genetic variability combines with environmental stimuli to influence disease susceptibility. The goal of this multi-PI grant is to advance the field toward genomic medicine for common forms of heart failure. It is well established that global changes in gene expression accompany the transition through cardiac hypertrophy and on to failure in animals and humans, causing cellular remodeling and deterioration of cardiac function. We reason that cues from the primary DNA sequence, modification of DNA (i.e. methylation) and chromatin-associated proteins (e.g. CTCF) and noncoding RNA (e.g. C5) combine to specify genomic structure and thereby gene expression. In this model, genomic conformation determines the range of phenotypic possibilities in an individual subjected to pathological stimuli by favoring some gene/protein expression profiles and disfavoring others. Our overall hypothesis is that epigenomic features, including DNA methylation and chromatin accessibility, set the baseline plasticity of chromatin structure and are influenced by genetics and environmental stimuli, such that some individuals are more susceptible than others to heart failure. We reason that global regulators of chromatin accessibility, including the novel epigenetic modifier C5 and the structural protein CTCF, play central roles in disease associated gene reprogramming. In the first aim, we will identify how transcription is regulated by the local chromatin landscape at genes, by dissecting the genetic contribution to DNA methylation (BS-seq) and chromatin accessibility (FAIRE- seq) in the normal and stressed heart. In the second aim, we will determine how intermediate chromatin domains are regulated in heart failure by exploring the role of a cardiac-specific lncRNA C5 to target deposition of heterochromatic histone modifications. In the third aim, we will identify the mechanisms of global chromatin conformation in cardiac health and disease by determining the involvement of the master genome architectural protein CTCF in cardiac phenotype. The long-term goals of these studies are to determine the mechanisms for how genetic variation controls differential disease susceptibility and to investigate epigenomic features as both biomarkers for cardiac pathology and causal components of cellular dysfunction.

Public Health Relevance

Cardiovascular disease is a scourge on human health for which transformative studies of its mechanisms are needed. This proposal will test the hypothesis that genome-wide changes in DNA methylation and chromatin accessibility together control heart failure susceptibility-furthermore, we will mechanistically reveal the roles of the lncRNA C5 and the master genome regulator CTCF in cardiac function. These investigations have the potential to establish new approaches for treating the diverse syndrome of heart failure in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL129639-03
Application #
9279236
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Luo, James
Project Start
2015-08-04
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$656,371
Indirect Cost
$206,369
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Rau, Christoph D; Vondriska, Thomas M (2017) DNA Methylation and Human Heart Failure: Mechanisms or Prognostics. Circulation 136:1545-1547
Monte, Emma; Fischer, Matthew A; Vondriska, Thomas M (2017) Epigenomic Disruption of Cardiovascular Care: What It Will Take. Circ Res 120:1692-1693
Gao, Chen; Wang, Yibin (2017) Untangle a Broken Heart via Janus Kinase 1. Circ Res 121:589-590
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Gao, Chen; Wang, Yibin (2016) Positive Role for a Negative Calcineurin Regulator in Cardiac Hypertrophy. Hypertension 67:841-2
Rau, Christoph D; Gao, Chen; Wang, Yibin (2016) Deconvolution of the Human Endothelial Transcriptome. Cell Syst 3:218-220
Touma, Marlin; Kang, Xuedong; Zhao, Yan et al. (2016) Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery. Circ Cardiovasc Genet 9:395-407
Karbassi, Elaheh; Monte, Emma; Chapski, Douglas J et al. (2016) Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation. Physiol Genomics 48:601-15
Wang, Jessica Jen-Chu; Rau, Christoph; Avetisyan, Rozeta et al. (2016) Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model. PLoS Genet 12:e1006038

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