GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE308nnn/GSE308865/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE308865GEOGSEfalseFLAG-tagged PITX2 CUT&TagAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an incurable condition linked to increased risks of stroke and heart failure. While common variations in the PITX2 non-coding region are the strongest genetic signature of AF risk, the role of this developmental left-right patterning transcription factor in AF remains a topic of debate. Here, we generated a mouse model (Pitx2Pro41Ser) of a common human PITX2 coding variant linked to increased AF risk in the Finnish population. These mice exhibit near-complete penetrance of pacing-induced AF, and transcriptional profiling indicates that Pitx2Pro41Ser is a loss-of-function mutation. In vivo cleavage under targets and tagmentation (CUT&Tag) reveals that PITX2 acts as a transcriptional repressor in developing left atrial (LA) cardiomyocytes (CMs). Ectopic Pitx2 expression in the postnatal right atrium (RA) CMs via adeno-associated virus (AAV) delivery or genetic overexpression represses RA genes and induces a LA transcriptome, revealing the remarkable plasticity of atrial CMs. Strikingly, delivery of Pitx2 AAV into Pitx2Pro41Ser mice rescues AF inducibility uncovering a direct link between PITX2 activity and AF susceptibility.2026/09/28GSE308865GSM9254758GSM9254759GSM9254761GSM925476034290308865Mus musculus