Uncovering the role of the epigenome in atrial remodelling underlying the transition from paroxysmal to permanent atrial fibrillation by Single Cell Omics

Atrial fibrillation (AF) is the most common persistent clinical tachyarrhythmia which starts as paroxysmal atrial fibrillation (PAF) and gradually progresses to permanent atrial fibrillation (PeAF). Current therapeutic strategies for AF are associated with relatively high recurrence and proarrhythmic side effects. Thus, there is a need for treatment limiting the cellular substrates for transition of PAF to PeAF. Several observations suggest a prominent role for epigenetic regulation in the promotion of AF although a direct link in mediating AF progression from PAF to PeAF remain poorly understood. My host laboratory recently showed that loss of EHMT1 and 2 and thus H3K9me2 contributes to hypertrophic remodeling of the cardiac ventricle. Whether this mechanism contributes to atrial remodeling is not determined. Therefore, the aim of the proposed project is to uncover the transcriptional changes that mediate the transition from PAF to PeAF and to determine the role of the epigenome in this transcriptome remodeling. Up until now analysis of atrial remodeling has been performed at the tissue level by bulk sequencing approaches. Atrial tissue however comprises a number of cell types that each participate in atrial remodeling during disease. By analyzing gene expression and epigeneome changes at the single cell level and in individual cell type, we aim to identify the relative contributions of changes to the phenotype of the atrial cardiac myocytes vs those of the phenotype and composition of the many other cell types of the atria such as fibroblasts. These new approaches will uncover new biology previously not accessible with bulk tissue analysis. Cell specific mechanisms uncover may form the basis for translation to effective therapies that may be used to prevent disease progress or reverse pathology