Research Description
Epigenetic mechanisms involved in complex human disease
As our understanding of the intricate mechanisms of gene regulation grows, it is apparent that (1) traditional methods of identifying aberrant genetic mechanisms associated with complex disease, such as linkage and association studies, will not be sufficient and (2) the paradigm where variants that lead to disease must exist within the coding region of a gene needs to be changed. One step towards better modeling of disease risk and understanding disease variants lies in expanding the paradigm of complex disease study to include epigenetic influences that contribute to disease. Methylation of CpG sites within DNA serves as one type of epigenetic cue which results in changes in gene function. The identification of methylated regions in the context of the human genome will define a relationship between the regulation/misregulation of epigenetic modifications and disease.
Current Projects
(1) To create comprehensive maps of the cytosine methylated genome in:
• human cardiovascular endothelial cells (diseased/non-diseased states)
• human cardiovascular smooth muscle cells (diseased/non-diseased states)
(2) Assess regions that change methylation state with disease in:
• peripheral blood cells from coronary artery disease patients and controls
• peripheral blood cells from patients with increased blood homocysteine levels
• diseased and non-diseased human aorta
(3) To map DNA methylation pattern changes caused by induction of hyperhomocysteinemia in vitro in endothelial cells and peripheral blood cells
(4) To determine the impact of aberrant methylation on endothelial cell and smooth muscle cell phenotype
DNA methylation is a mechanism utilized by the cell to control transcription through modification of chromatin structure and transcription factor binding. This type of transcriptional control allows for the heritable epigenetic inactivation of a gene, as well as temporal control of gene activation. DNA methylation plays a role in endothelial cell and smooth muscle cell phenotypic switching in response to atherosclerosis. Differentially methylated loci can be detected in activated versus inactivated endothelial cells (ESR2, SELE) and quiescent versus proliferative SMCs in culture (ESR1, ESR2, MCT3). The same changes have also been detected in atherosclerotic lesions (ESR1, ESR2, and MCT3). Identification of methylation patterns in these transitioning cells will lead to a better understanding of the complex interplay of the molecular mechanisms involved in CVD and will help to define molecular biomarkers that lead to lesion predisposition and lesion formation, as well as define the stages and the rate of disease progression. |
