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Profiling Genome-Wide DNA Methylation Patterns in Human Aortic and Mitral Valves

ABSTRACT: Cardiac valve structure and function are complex and include dynamic interactions between cells, extracellular matrix (ECM) and their hemodynamic environment. Valvular gene expression is tightly regulated by a variety of mechanisms including epigenetic factors such as histone modifications, RNA-based mechanisms and DNA methylation. To date, methylation fingerprints of non-diseased human aortic and mitral valves have not been studied. In this work we analyzed the differential methylation profiles of 12 non-diseased aortic and mitral valve tissue samples (in matched pairs). Analysis of methylation data (reduced representation bisulfite sequencing (RRBS)) of 1601 promoters genome-wide revealed 584 differentially methylated (DM) promoters, of which 13 were reported in endothelial mesenchymal trans-differentiation (EMT), 37 in aortic and mitral valve disease and 7 in ECM remodeling. Both functional classification as well as network analysis showed that the genes associated with the DM promoters were enriched for WNT-, Cadherin-, Endothelin-, PDGF- and VEGF- signaling implicated in valvular physiology and pathophysiology. Additional enrichment was detected for TGFB-, NOTCH- and Integrin- signaling involved in EMT as well as ECM remodeling. This data provides the first insight into differential regulation of human aortic and mitral valve tissue and identifies candidate genes linked to DM promoters. Our work will improve the understanding of valve biology, valve tissue engineering approaches and contributes to the identification of relevant drug targets.

PROVIDER: EGAS00001004559 | EGA |

REPOSITORIES: EGA

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Project description:Multiple molecular and cellular mechanisms are associated with the initiation and progression of aortic valve disease. Alterations in ECM remodeling, increased expression of pro-inflammatory cytokines, calcification, lipid deposition and changes in valve cell phenotype have demonstrated roles in development of aortic valve disease. Mechanical stimulation has a significant role in determining the physiological properties of valve tissue and an altered hemodynamic environment may result in pathological changes. We used microarrays to detail the global of gene expression profiles underlying valve remodeling during valve exposure to of two levels of cyclic mechanical pressure (normotensive 0-80mmHg and hypertensive 0-120mmHg ) on porcine valve tissue transcriptome using Sus Scrofa cDNA microarrays from Affymetrix and we identified distinct classes of up-regulated genes during this process. Hybridizations were carried out with RNA isolated from six independetn samples of valve tissue exposed to normotensive and hypertensive pressure for 24 hours at 1hz frecuency. Differentially expressed genes were identified by The t test with the option of unequal variance was used to calculate P values for each gene. The fold change and Q values for each gene were calculated with SAM program with permutation of 500 . Biological modeling of the differentially expressed genes (DE) was carried out based on GO groups and network analysis in ingenuity Pathway Analysis (IPA). Experiment Overall Design: The experimental design included three biological samples of porcine valve leaflets exposed to cyclic pressures of 0-80 or 0-120 mmHg for 24 hours, representing normotensive and hypertensive diastolic transvalvular pressure, respectively. Using Affymetrix porcine microarrays, we compared global gene expression profiles of aortic valve leaflets exposed to elevated and normal physiological pressure conditions . The effects of cyclic pressure on the transcriptome was determined by comparing the quantity and magnitud of change in gene expression levels of valve leflets, as well evaluating the molecular function each gene has in the cell,in the presence of hypertennsive (experimental) and normotensve pressurec (control).

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Profiling Genome-Wide DNA Methylation Patterns in Human Aortic and Mitral Valves

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