The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code

Area of Science:

• Molecular Biology
• Epigenetics
• Gene Regulation

Background:

• Endothelial nitric-oxide synthase (eNOS) mRNA expression is specific to endothelial cells in blood vessels.
• The chromatin environment surrounding the eNOS gene in expressing versus nonexpressing cells was investigated.

Purpose of the Study:

• To determine the role of chromatin modifications in the cell-specific expression of the eNOS gene.
• To investigate the functional relevance of histone modifications to eNOS gene transcription.

Main Methods:

• Assessed histone modifications (acetylation, methylation) at the eNOS core promoter and proximal regions in endothelial and nonendothelial cells.
• Utilized trichostatin A to inhibit histone deacetylase activity and methylthioadenosine to inhibit H3 lysine 4 methylation.
• Measured eNOS mRNA levels and RNA polymerase II loading.

Main Results:

• Endothelial cells showed enrichment of acetylated histones H3/H4 and methylated H3 lysine 4 at the eNOS promoter.
• Inhibition of histone deacetylase increased eNOS expression in nonexpressing cells.
• Inhibition of H3 lysine 4 methylation decreased eNOS expression and RNA polymerase II loading in endothelial cells.

Conclusions:

• Cell-specific histone modifications, including acetylation and methylation, are critical regulators of eNOS gene expression.
• These epigenetic marks establish a distinct chromatin environment that facilitates eNOS transcription in endothelial cells.