Diabetes mellitus, independent of coronary artery disease, hypertension, or other risk factors, is associated with up to a 4-fold increase in risk of developing heart failure (HF). While other etiologies of heart failure have effective therapeutics such as diuretics and inotropes, diabetic HF is often resistant or unresponsive to these. Thus, the development of targeted therapies to address the underlying cardiac pathology unique to diabetic HF is essential. Clinical evidence suggests that diabetic hyperglycemia imparts long term elevated risks for heart failure, even after correction. Dr. Wende?s laboratory tests the hypothesis that this aberrant glucose flux, as seen in diabetes mellitus, contributes to the development of cardio-metabolic dysfunction via epigenetic changes. Recent work in his laboratory has detected a distinct signature of promoter-associated DNA demethylation in human diabetic HF that corresponds with inversely altered transcriptional activity. Specifically, using both RNA-sequencing and Illumina Methy450K array studies on cardiac biopsies taken during surgery, we found the transcription factor early growth response 2 (EGR2) had significant decreases in promoter methylation and a concurrent increase in transcript levels unique to HF samples from diabetic patients. Similarly, both RNA-sequencing and bisulfite treated DNA sequencing of cardiac tissue from diabetic mice revealed the same pattern of hypomethylation and increased expression of Egr2. Relatively little is known about the transcription factor EGR2 in the heart, as significant previous work has focused on its regulation of neuronal myelination in the context of nerve development and response to nerve injury. However, recent reports have highlighted a possible role for EGR2 in regulating cardiac hypertrophy in response to pressure overload, and other papers have shown that EGR2 plays a pro-fibrotic role in systemic sclerosis. Therefore, we hypothesize that EGR2 is a nodal transcription factor which mediates diabetes-associated cardiac dysfunction, fibrosis, and hypertrophy in response to demethylation of its promoter. This proposal will test the following three aims: (1) Determine whether EGR2 expression is sufficient to induce cardiac dysfunction, fibrosis, and hypertrophy noted in diabetic mice, (2) determine whether EGR2 expression is necessary for the cardiac dysfunction, fibrosis, and hypertrophy noted in diabetic mice, and (3) determine whether transcriptional activation of Egr2 is dependent on promoter DNA methylation. In summary, determining whether EGR2 is a novel transcription regulator of cardiac function may define a novel mechanism through which the heart could be epigenetically reprogramed to reverse the toxic effects of hyperglycemia in diabetic heart failure.
Heart failure is a widespread and severe clinical consequence of poorly treated diabetes mellitus. Preliminary work has defined an association between DNA methylation, a molecular tag implicated in the regulation of gene expression, and diabetic heart failure; however, the downstream functional effects of genes differentially methylated in the diabetic heart remains poorly understood. This proposal aims to determine whether EGR2, a transcription factor elevated and demethylated in the diabetic heart, and with known roles in fibrosis, impacts cardiac dysfunction and fibrosis through transcriptional remodeling and in response to DNA demethylation.
