Left-right asymmetry and PITX2 in atrial fibrillation

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PROJECT SUMMARY Atrial fibrillation (AF) is the most common sustained arrhythmia in the United States with a 25% lifetime risk, and accounts for one-third of all cardiovascular diseases. Treatment and care associated with AF costs roughly $26 billion/year in the United States alone 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 paired-like homeodomain transcription factor (TF), PITX2, have been resoundingly linked to AF risk. PITX2 is best 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, the first aim proposes to investigate the Pitx2-dependent DNA methylome in left-right determination. Left-right asymmetry established in gastrulation leads to Pitx2 expression in the left but not right atria. I have uncovered that the left-right DNA methylation patterning differences occur at PITX2 sites, suggesting PITX2 regulates DNA methylation. In the second aim, I will investigate the role of PITX2 left-right patterning in oxidative stress response and homeostasis. The PV delivers oxygen-rich blood, the only vein to do so, to the LA from the lungs, creating a physiological distinction in oxygenation between left and right. Oxygen-rich environments are prone to oxidative stress, contributing to AF risk. Preliminary work identified a novel interaction between PITX2 and the oxidative response factor, OXR1, in the LA, and previous work implicates PITX2 in oxidative stress response following ischemia through stress-response TF, NRF2. This aim is designed to illuminate the role of PITX2 in mediating oxidative stress and the development of AF, a tractable pathway for early intervention. In the final aim, I will investigate the molecular mechanisms of PITX2 transcriptional repression. Predominantly, PITX2 acts as a repressor in the LA. I identified a novel interaction between PITX2 and the COPRS-PRMT5 arginine methyltransferase complex capable of histone H4R3 methylation, a repressive mark. Furthermore, PRMT5-dependent H4R3 methylation can be reversed, suggesting a mechanism of tunable gene expression by PITX2. 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.