Single-cell chromatin profiling reveals genetic programs activating proregenerative states in nonmyocyte cells

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Molecular Biology

Background:

• Cardiac regeneration involves complex cell-cell communication and transient cell state activation.
• While cell origins and characteristics are known, the underlying signaling and genetic programs remain unclear.

Purpose of the Study:

• To investigate the extracellular signaling and intrinsic genetic programs governing transient cell state activation in cardiac regeneration.
• To define regulatory architectures and intercellular communication principles in zebrafish heart regeneration.

Main Methods:

• Single-cell chromatin landscape analysis of noncardiomyocytes in regenerating zebrafish hearts.
• Inference of cis-regulatory architectures and trans-acting factors.
• Motif analysis and cell-specific genetic manipulations.

Main Results:

• Delineated chromatin landscapes of noncardiomyocytes at single-cell resolution.
• Identified tumor necrosis factor-alpha (a macrophage-derived inflammatory signal) acting via activator protein-1.
• Demonstrated cooperative function of tumor necrosis factor-alpha and other regulators in activating critical noncardiomyocyte cell types.

Conclusions:

• Defined the regulatory architectures controlling cell type-specific gene expression in zebrafish heart regeneration.
• Elucidated intercellular communication principles involving inflammatory signals in cardiac repair.
• Highlighted the cooperative roles of transcription factors and external signals in activating proregenerative cell states.