Decoding the PITX2-controlled genetic network in atrial fibrillation

JCI Insight. 2022 Jun 8;7(11):e158895. doi: 10.1172/jci.insight.158895.

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.

Keywords: Arrhythmias; Cardiology; Epigenetics; Transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atrial Fibrillation* / genetics
  • Atrial Fibrillation* / metabolism
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Gene Regulatory Networks
  • Heart Atria / metabolism
  • Homeobox Protein PITX2
  • Homeodomain Proteins* / genetics
  • Homeodomain Proteins* / metabolism
  • Humans
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • BMP10 protein, human
  • Bone Morphogenetic Proteins
  • Homeodomain Proteins
  • Transcription Factors