Acute NelfA knockdown restricts compensatory gene expression and precipitates ventricular dysfunction during cardiac...

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Gene Regulation

Background:

• The balance of transcription complexes regulates gene expression in the heart under normal and hypertrophic conditions.
• The Negative Elongation Factor (NELF) complex, including NELF-A (Whsc2), is involved in RNA polymerase II (Pol II) pausing.
• Understanding NELF-A's role in cardiac hypertrophy is essential for comprehending cardiac gene regulation.

Purpose of the Study:

• To investigate the function of NELF-A (Whsc2) in the heart during pressure-overload induced hypertrophy.
• To determine NELF-A's association with gene promoters and its impact on Pol II occupancy.
• To elucidate the role of NELF-A in regulating gene expression during cardiac hypertrophy.

Main Methods:

• Genome-wide occupancy analysis of NELF-A, Pol II, TFIIB, and H3K9ac in control and hypertrophied hearts.
• In vivo knockdown of NELF-A in pressure-overloaded hearts.
• In vitro knockdown of NELF-A in cardiomyocytes.

Main Results:

• NELF-A associates with active gene promoters, including essential and cardiac-enriched genes.
• De novo NELF-A recruitment occurs at inducible gene promoters during hypertrophy, correlating with increased gene expression.
• NELF-A knockdown leads to ventricular dysfunction and decreased expression of inducible and cardiac-enriched genes.

Conclusions:

• Promoter NELF-A occupancy is essential for Pol II-dependent transcription.
• NELF-A plays a critical role in regulating active transcription and gene expression during cardiac hypertrophy.
• NELF-A is required for maintaining cardiac function and gene expression during hypertrophy.