Left-right asymmetry and PITX2 in atrial fibrillation

About This Grant

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common sustained arrhythmia in the United States at 5% of the population and 1-in-3 lifetime risk. Treatment and care associated with AF costs over $26 billion/year in the US and accounts for 10% of all Medicare spending. Debilitating complications linked to AF include heart failure and stroke. The molecular links between genetics and AF disease risk are not well understood and pose a significant knowledge gap for curative therapies and patient care. Common coding and regulatory variations of the transcription factor (TF), PITX2, have been resoundingly linked to AF risk. PITX2 is known for regulating left-right asymmetry during development. In the heart, PITX2 is expressed in the left atrial (LA) and pulmonary vein (PV) myocardium, the most common trigger sites for AF. Mouse models of reduced Pitx2 are susceptible to AF, and my recent work describes how decreased Pitx2 perturbs TF networks and hints at a developmental origin of AF risk; however, the mechanism is unknown. The central hypothesis for this study is that PITX2 drives left-sided fate determination through epigenetic remodeling, which imparts long-lasting transcriptional consequences underlying adult disease. To address this hypothesis: 1. Investigate the Pitx2-dependent DNA methylome during left-right determination, analyzing observed DNA methylation pattern differences at PITX2 binding sites. 2. Examine the role of PITX2 in oxidative stress response and homeostasis, considering the unique oxygen-rich environment of the PV and preliminary findings of PITX2 interactions with factors associated with the DNA damage response. 3. Elucidate the epigenetic mechanisms of reversible PITX2-mediated transcriptional repression, focusing on PRMT5 mediated-histone modifications. Altogether, the proposed project aims to understand the role of PITX2 in epigenetic patterning of the LA in context of AF. The proposed study takes a novel approach to interrogating the PITX2 gene regulatory network and develops several new reagents and datasets for the field. Furthermore, through this work, I hope to gain insights for more targeted approaches in AF patient care.