Laboratory of Cardiac Epigenome, Molecular Epigenetics and Stress-gene Response.
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. Moreover, current therapy slows disease progression, but does not reverse the course of disease. Although heart failure 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.
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 deep dive and to establish the role of the cardiac epigenome and chromatin reorganization in heart failure onset and progression. To achieve this, 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. Epigenetic tools represent a real potential for finding refreshing molecular therapeutic approaches that work to reverse the course of disease, rather than just slowing down its progression.
The recent large BMRC SPF Cardiovascular Research grant award consists of a Genetics/Epigenetics theme which our group leads. This has the ambitious aim of mapping out functional elements in the cardiac genome and epigenome, opening up a new and important area of cardiovascular research. We hope that all together 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.
- Kam S, Bylstra Y, Forrest L, Macciocca I, Foo R "Experience of Asian males communicating cardiac genetic risk within the family." J Community Genet 2018 Jul ; 9(3) : 293-303 Abstract
- Zhao RR, Ackers-Johnson M, Stenzig J, Chen C, Ding T, Zhou Y, Wang P, Ng SL, Li PY, Teo G, Rudd PM, Fawcett JW, Foo RSY "Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling." Circulation 2018 Jun 05 ; 137(23) : 2497-2513 Abstract
- Bylstra Y, Kuan JL, Lim WK, Bhalshankar JD, Teo JX, Davila S, Teh BT, Rozen S, Tan EC, Liew WKM, Yeo KK, Tan P, Saw SM, Cheng CY, Cook S, Foo R, Jamuar SS "Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders." Genet Med 2018 Jul 02 Abstract
- Tan WL, Lim BT, Anene-Nzelu CG, Ackers-Johnson M, Dashi A, See K, Tiang Z, Lee DP, Chua WW, Luu TD, Li PY, Richards AM, Foo RS "A landscape of circular RNA expression in the human heart." Cardiovasc Res 2017 Mar 01 ; 113(3) : 298-309 Abstract
- See K, Tan WLW, Lim EH, Tiang Z, Lee LT, Li PYQ, Luu TDA, Ackers-Johnson M, Foo RS "Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo." Nat Commun 2017 08 09 ; 8(1) : 225 Abstract
- Jamuar SS, Kuan JL, Brett M, Tiang Z, Tan WL, Lim JY, Liew WK, Javed A, Liew WK, Law HY, Tan ES, Lai A, Ng I, Teo YY, Venkatesh B, Reversade B, Tan EC, Foo R "Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?" EBioMedicine 2016 Mar ; 5 : 211-6 Abstract
- Ackers-Johnson M, Li PY, Holmes AP, O\'Brien SM, Pavlovic D, Foo RS "A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart." Circ Res 2016 Sep 30 ; 119(8) : 909-20 Abstract
- Siggens L, Figg N, Bennett M, Foo R "Nutrient deprivation regulates DNA damage repair in cardiomyocytes via loss of the base-excision repair enzyme OGG1." FASEB J 2012 May ; 26(5) : 2117-24 Epub 2012 Feb 1 Abstract
- Haider S, Cordeddu L, Robinson E, Movassagh M, Siggens L, Vujic A, Choy MK, Goddard M, Lio P, Foo R "The landscape of DNA repeat elements in human heart failure." Genome Biol 2012 Oct 3 ; 13(10) : R90 Epub 2012 Oct 3 Abstract
- Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T, Siggens L, Vujic A, Simeoni I, Penkett C, Goddard M, Lio P, Bennett MR, Foo RS "Distinct epigenomic features in end-stage failing human hearts." Circulation 2011 Nov 29 ; 124(22) : 2411-22 Epub 2011 Oct 24 Abstract