Function of Pitx2 in postnatal heart

Pitx2 is the homeobox gene located in proximity to the human 4q25 familial atrial fibrillation locus. Pitx2 haploinsufficient mice are prone to pacing induced atrial fibrillation indicating that reduced Pitx2 promotes an arrhythmogenic substrate within the atrium. Here, we inactivated Pitx2 in postnatal heart and discovered that unstressed adult Pitx2 mutant mice had sinus node dysfunction with impaired atrial conduction, an arrhythmia closely associated with atrial fibrillation. A genome-wide search for Pitx2 transcriptional targets using ChIP-sequencing and RNA expression profiling shows that Pitx2 represses target genes encoding cell junction proteins, ion channels, and critical transcriptional regulators many of which have been implicated in human atrial fibrillation by genome wide association studies. Our findings unveil a Pitx2 postnatal arrhythmogenic function, novel Pitx2 target genes relevant to atrial fibrillation, and reveal that Pitx2 stabilizes the intercalated disc in postnatal atrium. Genomic occupancy profiling of transcriptional factor Pitx2 in postnatal heart.

Pitx2是位于人类4q25家族性心房颤动位点附近的同源框基因（homeobox gene）。Pitx2单倍剂量不足小鼠易发生起搏诱发性心房颤动，提示Pitx2表达下调可促进心房内致心律失常底物的形成。本研究中，我们在出生后心脏中敲除Pitx2，发现未受应激的成年Pitx2突变小鼠存在窦房结功能障碍伴心房传导受损，这类心律失常与心房颤动密切相关。通过染色质免疫共沉淀测序（ChIP-sequencing）与RNA表达谱分析开展的Pitx2转录靶基因全基因组筛选显示，Pitx2可抑制编码细胞连接蛋白、离子通道及关键转录调控因子的靶基因，其中诸多基因已通过全基因组关联研究（genome wide association studies）被证实与人类心房颤动相关。本研究结果揭示了Pitx2在出生后阶段的致心律失常功能，发现了与心房颤动相关的新型Pitx2靶基因，并证实Pitx2可稳定出生后心房的闰盘（intercalated disc）。本数据集包含出生后心脏中转录因子Pitx2的基因组占据谱分析数据。