Decoding the PITX2-controlled genetic network in atrial fibrillation.

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Genomics

Background:

• Atrial fibrillation (AF) is a common arrhythmia and stroke risk factor, often originating from pulmonary veins (PVs).
• Sequence variants in regulatory elements of the PITX2 transcription factor gene are associated with AF predisposition.
• PITX2 is crucial for cardiomyocyte (CM) development and function in the PV and left atrium (LA).

Purpose of the Study:

• To investigate the molecular mechanisms underlying AF predisposition linked to PITX2 in PV and LA CMs.
• To identify distinct CM cell states and their regulatory networks in the PV and LA.
• To explore how PITX2 mutations affect gene expression and cell signaling in cardiac contexts.

Main Methods:

• Single nuclei multiomic profiling (RNA and chromatin accessibility).
• Spectral clustering for cell state identification.
• Analysis of gene expression changes and cis-regulatory grammars in Pitx2-mutant CMs.

Main Results:

• Distinct PV- and LA-enriched CM cell states were identified.
• Pitx2 mutations altered gene expression in PV and LA CMs, leading to cardiac dysfunction.
• Perturbed gene networks in mutant CMs were enriched with AF predisposition genes, suggesting combinatorial risk.
• Mutant PV and LA CMs exhibit pathogenic BMP10 signaling to other cardiac cell types.

Conclusions:

• PITX2-directed cis-regulatory grammars are cell-type specific and critical for CM function in PV and LA.
• Altered gene expression and signaling in response to PITX2 dysfunction contribute to AF pathogenesis.
• This multiomic framework elucidates the molecular basis of AF predisposition in human PVs.