A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene...

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Heart failure (HF) is strongly associated with atrial fibrillation (AF), affecting up to 50% of HF patients.
• Atrial remodeling is the presumed mechanism linking HF and AF.
• Upregulation of the transcription factor FOG2 (friend of GATA2) occurs in human ventricles during HF and induces HF in mice.

Purpose of the Study:

• To investigate the role of FOG2 in the atria during heart failure.
• To determine if FOG2 directly contributes to atrial fibrillation development in the context of HF.

Main Methods:

• Assessed FOG2 expression in human atria.
• Utilized adult cardiomyocyte-specific FOG2 overexpression in mice.
• Performed comprehensive electrophysiology, calcium flux, gene expression, and genomic analyses.
• Developed a novel method for defining transcription factor interactions via enhancer noncoding transcription.

Main Results:

• FOG2 is significantly upregulated in human atria during HF.
• FOG2 overexpression in mice induced spontaneous atrial fibrillation prior to HF or atrial remodeling.
• FOG2 disrupted cardiomyocyte calcium cycling and repressed TBX5-driven atrial gene expression.
• FOG2 interacts with GATA4 and TBX5 in a shared atrial gene regulatory network.

Conclusions:

• HF-induced transcriptional changes in the atria antagonize the atrial rhythm gene regulatory network.
• This provides a genomic link between HF and AF risk, independent of atrial remodeling.
• FOG2 plays a direct role in promoting AF through transcriptional dysregulation.