HOPX-associated molecular programs control cardiomyocyte cell states underpinning cardiac structure and function

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Genomics

Background:

• Cardiac development relies on precise genomic regulation of cardiomyocyte differentiation.
• The role of non-DNA-binding proteins like HOPX in this process is not fully understood.

Purpose of the Study:

• To investigate the genomic regulatory function of the homeodomain protein HOPX in cardiomyocyte differentiation and function.
• To elucidate the upstream regulators and downstream targets of HOPX in cardiac gene programs.

Main Methods:

• Utilized human-induced pluripotent stem cell-derived cardiomyocytes for loss-of-function studies.
• Performed in vitro perturbation studies to analyze cell growth and proliferation effects on HOPX.
• Employed cell, organoid, and zebrafish regeneration models to assess HOPX function in development and disease.

Main Results:

• HOPX interacts with and regulates cardiac genes and enhancer networks crucial for heart development.
• Upstream cell growth and proliferation signals modulate HOPX transcription, thereby controlling cardiac gene programs.
• HOPX-regulated gene programs are critical for cardiomyocyte function during development and in disease contexts.

Conclusions:

• Mechanistically links cell signaling pathways to HOPX transcription as a key regulator of cardiomyocyte identity.
• Demonstrates HOPX's vital role in controlling gene programs essential for cardiac development, function, and regeneration.