Silencing transcription factors such as CREB3L2, BNC2, and NFAT5 modulated the induction of extracellular matrix gene expression by human cardiac fibroblasts.
Identifies novel transcription factors, including CREB3L2, BNC2, and NFAT5, that regulate cardiac fibrosis, providing potential new therapeutic targets for heart disease.
BACKGROUND: Cardiac fibrosis is a major cause of cardiac dysfunction and is associated with virtually all forms of heart disease. Recently, single-cell genomic approaches have revealed in unprecedented resolution the orchestrated cellular responses driving cardiac fibrosis. Yet, the fibrosis-inducing phenotypes that emerge in the heart after nonischemic cardiac stress and the transcriptional circuits that govern fibrogenic cellular phenotypes are not well understood. METHODS: Applying a single-cell paired-multiomic approach-by which both transcriptomic and epigenetic information is captured from individual cells-we reveal key transcription factors, in mouse and human hearts, associated with fibrosis development after nonischemic cardiac insults. Using high-throughput bulk transcriptomic and proteomic analyses, microscopy, and functional in vitro assays, we validate the distinct roles of new and established transcription factors in cardiac fibrosis. RESULTS: Analysis of mouse hearts undergoing reverse remodeling after angiotensin II stimulation, where cardiac fibrosis dissipates, we find these factors are reversibly activated. Further, silencing transcription factors-including those we have identified that are previously unlinked to cardiac fibrosis, such as CREB3L2, BNC2, and NFAT5-modulates induction of extracellular matrix gene expression by human cardiac fibroblasts. Detailed analysis of CREB3L2 showed that it regulates cardiac fibrosis by modulating extracellular matrix synthesis through a dual mechanism-involving its N-terminal transactivation domain and a paracrine-acting C-terminal fragment-which is triggered after endoplasmic reticular stress. CONCLUSIONS: This study identifies critical transcription factors regulating cardiac fibrosis and offers promising new targets to ameliorate the development of fibrosis in the context of stressors that cause cardiac dysfunction.
Krstevski et al. (Wed,) conducted a other in Cardiac fibrosis. Silencing transcription factors (CREB3L2, BNC2, NFAT5) was evaluated on Induction of extracellular matrix gene expression. Silencing transcription factors such as CREB3L2, BNC2, and NFAT5 modulated the induction of extracellular matrix gene expression by human cardiac fibroblasts.