Heart Failure Epigenomics, Molecular Epigenetics and Stress-Gene Response

This theme is led primarily by Associate Professor Roger Foo.

Heart failure is a major cause of mortality and morbidity in the world today. Easily rivalling the severity of some forms of cancer, life expectancy for patients with heart failure at 5 years can be as  poor as <50%. Novel targets are urgently needed for the heart failure drug discovery pipeline. Although the disease can be caused by different originating causes including hypertension, diabetes, myocardial infarction and genetic mutations, it is nonetheless characterised by convergent processes such as fibrosis, angiogenesis and cell death. Similarly a consistent pattern of gene expression constitutes the myocardial genomic stress-response in the progression of heart failure. A hallmark for this myocardial genomic stress-response includes fetal gene reprogramming, upregulation of extracellular matrix genes and others. However whether the generic genomic stress response is only consequential or exactly which part of it contributes to disease progression remains to be clarified. 

The epigenome refers to “marks” on the genome including histone modifications and DNA methylation. Our group published the first evidence that differential DNA methylation exists in end-stage human cardiomyopathic hearts and correlates to changes in specific gene expression. By high-throughput sequencing, we have also published the first glimpse of genome-wide DNA methylation landscapes of the failing human heart. A major effort in the lab now is to examine the cause and effect of altered DNA methylation, and to establish the role of the cardiac epigenome and chromatin reorganization in heart failure onset and progression. We employ a host of genomic and molecular tools, with tractable in vitro and in vivo experimental models as well as human explant tissue to study the myocardial genomic and epigenomic stress response.

Our group now leads the Genetics/Epigenetics theme of a $30M BMRC SPF research grant with the ambitious aim of maping out functional elements in the cardiac genome and epigenome. This programme opens up a new and important area of cardiovascular research. We hope that our work will eventually lead to the identification of novel targets for future heart failure therapy.

In a separate translational programme, our lab was also responsible for establishing Singapore’s first Inherited Cardiac Conditions clinic based at the National University Heart Centre. This clinic makes use of high-throughput sequencing-based genetic test panels developed at the Genome Institute of Singapore.