GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE309nnn/GSE309394/primary200OKMethylation profilingMus musculusMethylation profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE309394GEOGSEfalseEmbryonic left atrial Pitx2 mutant and control WGBSAtrial 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.2026/09/28GSE309394GSM9266790GSM9266791GSM9266792GSM9266793GSM9266794GSM9266795GSM9266796GSM9266797GSM9266798GSM9266787GSM9266788GSM926678924247309394Mus musculus