Publication Date

6-8-2022

Journal

JCI Insight

DOI

10.1172/jci.insight.158895

PMID

35471998

PMCID

PMC9221021

PubMedCentral® Posted Date

6-8-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Atrial Fibrillation, Bone Morphogenetic Proteins, Gene Regulatory Networks, Heart Atria, Homeodomain Proteins, Humans, Transcription Factors, Homeobox Protein PITX2, Arrhythmias, Epigenetics, Transcription

Abstract

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia and a major risk factor for stroke, often arises through ectopic electrical impulses derived from the pulmonary veins (PVs). Sequence variants in enhancers controlling expression of the transcription factor PITX2, which is expressed in the cardiomyocytes (CMs) of the PV and left atrium (LA), have been implicated in AF predisposition. Single nuclei multiomic profiling of RNA and analysis of chromatin accessibility combined with spectral clustering uncovered distinct PV- and LA-enriched CM cell states. Pitx2-mutant PV and LA CMs exhibited gene expression changes consistent with cardiac dysfunction through cell type-distinct, PITX2-directed, cis-regulatory grammars controlling target gene expression. The perturbed network targets in each CM were enriched in distinct human AF predisposition genes, suggesting combinatorial risk for AF genesis. Our data further reveal that PV and LA Pitx2-mutant CMs signal to endothelial and endocardial cells through BMP10 signaling with pathogenic potential. This work provides a multiomic framework for interrogating the basis of AF predisposition in the PVs of humans.

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