Pitx2 in atrial fibrillation

描述(由申请人提供)：Pitx2同源结构域转录因子是左右不对称的中心转录调节因子，在心脏内起到抑制心脏形态发生的作用。现在很明显，Pitx2基本上与房颤有关，尽管这种联系的基础仍然不清楚。Pitx2-房颤关联的第一个证据是在基因组广泛关联研究中提出的，即染色体4q25的一个区域与早发性家族性房颤有关。Pitx2是与疾病相关的单核苷酸多态(SNP)最接近的基因。携带4q25SNP的房颤患者无高血压、糖尿病和瓣膜缺陷。此外，携带4q25SNP的患者更容易发生心源性中风，进一步迫切需要深入了解与4q25SNP相关的潜在分子机制。我们是第一个报告Pitx2杂合子小鼠易患房颤的小组，这表明降低了Pitx2水平会导致房颤。三个不同的小组随后重复了我们的发现。由于其在房颤中的关键作用，我们推测，对Pitx2转录靶基因的全基因组分析将为深入了解房颤发生的分子机制提供新的和根本重要的见解。我们的初步染色质免疫沉淀(CHIP)序列(SEQ)数据表明，Pitx2直接与许多与房颤和PR间期有关的基因结合在一起。此外，对ChIPseq数据的基序分析进一步表明，Pitx2与其他与房颤有关的转录因子如NKX2.5协调调节基因表达。最后，我们的芯片序列和其他初步数据表明，Pitx2调控着对房颤易感性至关重要的microRNAs。我们建议深入研究Pitx2调控传导系统发展和维持的分子基础。目前对房颤的遗传机制了解甚少。新的基因洞察力将对未来的诊断测试和家庭咨询至关重要。此外，随着人类基因组测序变得越来越普遍，对房颤遗传学的深入了解将为患者管理提供关键资源。最后，有一个长期目标是基于坚实的科学信息开发新的治疗策略，这些信息将来自模式生物和人类遗传学的工作。

DESCRIPTION (provided by applicant): The Pitx2 homeodomain transcription factor is a central transcriptional regulator in left right asymmetry that functions within the heart to contro cardiac morphogenesis. It is now clear that Pitx2 is fundamentally connected to AF although the basis for this connection remains obscure. The first evidence for the Pitx2-AF link was made in a Genome Wide Association Study (GWAS) implicating a region of chromosome 4q25 in early onset familial AF. Pitx2 was the gene in closest proximity to the disease associated single nucleotide polymorphism (SNP). AF patients with the 4q25 SNP were free of hypertension, diabetes and valve defects. Moreover, patients with the 4q25 SNP were more prone to cardioembolic stroke adding further urgency to gain insight to the underlying molecular mechanisms associated with the 4q25 SNP. We were the first group to report that Pitx2 heterozygous mice were predisposed to AF indicating that reduced levels of Pitx2 led to AF. Three different groups have subsequently replicated our findings. Because of its critical role in AF, we hypothesized that genome wide analysis of Pitx2 transcriptional target genes would provide novel and fundamentally important insight into the molecular mechanisms for AF in the Pitx2 haplo-insufficient state. Our preliminary Chromatin Immuno Precipitation (ChIP) sequence (seq) data indicate that Pitx2 directly binds to a number of genes that have been implicated in AF and also PR interval in human GWAS studies. Moreover, motif analysis of our ChIPseq data further suggests that Pitx2 coordinately regulates gene expression with other transcription factors such as Nkx2.5 that are implicated in AF. Lastly, our ChIP seq and other preliminary data suggest that Pitx2 regulates microRNAs that are important for AF predisposition. We propose to thoroughly investigate the molecular basis for Pitx2 regulated conduction system development and maintenance. There is poor understanding of the genetic mechanisms underlying AF. New genetic insights will be critical for diagnostic testing and family counseling i the future. Moreover, an in depth knowledge of genetics of AF will provide critical resources for patient management as human genome sequencing becomes more commonplace. Finally, there is the long term goal to develop novel therapeutic strategies based on solid scientific information that will come from work in model organisms and human genetics.