Cardiac cell type-specific gene regulatory programs and disease risk association

Area of Science:

• Genomics
• Cardiovascular Biology
• Epigenetics

Background:

• Misregulated gene expression in the heart causes cardiovascular diseases, a leading cause of death.
• Understanding the genomic location of cis-regulatory elements (cCREs) in cardiac cells is crucial for disease research.

Purpose of the Study:

• To map candidate cis-regulatory elements (cCREs) in distinct human heart chambers at single-cell resolution.
• To identify cCREs and transcription factors associated with specific cardiac cell types and heart failure.
• To investigate the role of genetic variants within cCREs in cardiovascular diseases.

Main Methods:

• Single-cell genomics to identify and map >287,000 cCREs across four human heart chambers.
• Analysis of cCREs and associated transcription factors in different cardiac cell types and conditions (health vs. heart failure).
• Enrichment analysis of cardiovascular disease-associated genetic variants within identified cCREs.

Main Results:

• A comprehensive atlas of >287,000 human cardiac cCREs was generated at single-cell resolution.
• Region-specific and cell type-specific cCREs and transcription factors were identified, varying with heart failure.
• Cardiovascular disease variants, including 38 atrial fibrillation variants, were found enriched in cardiomyocyte cCREs.
• Functional validation showed two variants impact a cCRE regulating KCNH2/HERG expression and cardiac action potential.

Conclusions:

• The cardiac cCRE atlas provides a foundational resource for understanding cell type-specific gene regulation in the human heart.
• This resource facilitates research into the genetic basis of cardiovascular diseases and potential therapeutic targets.
• The findings highlight the importance of non-coding regulatory regions in cardiac function and disease etiology.