Effects of the atrial fibrillation risk region on chromosome 4q25 and PITX2 on atrial metabolic and mitochondrial function

心房颤动（AF）影响了德国至少2%的人口。它是心血管死亡、中风、心力衰竭和急性冠状动脉综合征患者的一个非常普遍的危险因素。在人群中，4q25染色体上的常见基因变异显示出与房颤风险最强的基因组关联。这些风险变异存在于通过远程染色质相互作用控制配对样同源结构域2 （PITX2）基因转录的增强子区域。PITX2的表达主要局限于成人心脏的左心房。包括这些风险变异在内的增强子缺失导致消融后复发性房颤的小鼠和患者心房PITX2表达减少，心房电功能的改变和心房电功能和收缩功能的改变使房颤易感性增加。为了了解这种心房疾病表型的分子机制，本项目旨在表征敲入小鼠和基因工程增强子缺失的人诱导多能干细胞来源的心房心肌细胞（心房hiPSC-EHTs）模型在三维组织培养格式中培养的电生理和代谢后果。实验将包括超声心动图和小鼠光学起搏，以及心房hiPSC-EHTs营养限制期间的收缩分析，并结合无偏倚的转录组学和代谢分析。这些结果有望增强我们对房颤潜在疾病机制的理解，并可能激发新的治疗策略。

Atrial fibrillation (AF) affects at least 2% of the population in Germany. It is a highly prevalent risk factor for cardiovascular deaths, stroke, heart failure, and acute coronary syndromes in patients. Common gene variants on chromosome 4q25 show by far the strongest genomic association with AF risk in the population. These risk variants reside in an enhancer region controlling transcription of the Paired like Homeodomain 2 (PITX2) gene via long-range chromatin interactions. PITX2 expression is largely confined to the left atrium in the adult heart. Enhancer deletion including these risk variants leads to reduced atrial PITX2 expression in mice and in patients to recurrent AF after ablation, predisposition to AF by modifying electrical function of the atria and alterations in atrial electrical and contractile function. To understand the molecular mechanisms of this atrial disease phenotype, the present project aims to characterize the electrophysiological and metabolic consequences of enhancer deletion in a knockin-in mouse and in genetically-engineered enhancer deleted human induced pluripotent stem cell-derived atrial cardiomyocyte (atrial hiPSC-EHTs) model cultured in a three-dimensional tissue culture format. Experiments will involve echocardiography and optical pacing in mice as well as contractile analysis during nutrient-restriction in atrial hiPSC-EHTs combined with unbiased transcriptomic and metabolic analysis. The results are anticipated to enhance our understanding of underlying AF disease mechanisms and might inspire novel treatment strategies.