Conserved Transcriptional Circuits Regulate Cardiac Fibroblast-Mediated Fibrosis

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Epigenetics

Background:

• Cardiac fibrosis is a primary driver of cardiac dysfunction across various heart diseases.
• While single-cell genomics has advanced understanding, the specific fibrogenic phenotypes and transcriptional circuits post-nonischemic stress remain unclear.

Purpose of the Study:

• To identify key transcription factors regulating cardiac fibrosis development after nonischemic stress.
• To elucidate the transcriptional circuits governing fibrogenic cellular phenotypes in mouse and human hearts.

Main Methods:

• Employed a single-cell paired-multiomic approach to capture transcriptomic and epigenetic data.
• Utilized high-throughput bulk transcriptomics, proteomics, microscopy, and in vitro assays for validation.

Main Results:

• Identified novel transcription factors (CREB3L2, BNC2, NFAT5) linked to cardiac fibrosis.
• Demonstrated that silencing these factors modulates extracellular matrix gene expression in cardiac fibroblasts.
• Detailed CREB3L2's dual mechanism in regulating cardiac fibrosis via endoplasmic reticular stress.

Conclusions:

• Pinpointed critical transcription factors that regulate cardiac fibrosis.
• Proposed these factors as promising therapeutic targets to mitigate fibrosis and cardiac dysfunction.