Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27 Acetylation.

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• Histone H3 lysine 27 acetylation (H3K27Ac) is a known marker for enhancer activity.
• The precise functional role of H3K27Ac at enhancers remains largely unclear.
• Enhancers are crucial regulatory elements controlling gene expression.

Purpose of the Study:

• To investigate the functional significance of H3K27Ac at enhancers.
• To dissect the role of H3K27Ac in enhancer-regulated gene networks.
• To explore the impact of blocking CBP/P300 bromodomain function on H3K27Ac and enhancer activity.

Main Methods:

• Utilized a chemical genetics strategy to acutely inhibit the cAMP response element binding protein (CREB) binding protein (CBP)/P300 bromodomain.
• Employed models of hematological malignancies to study the effects of bromodomain inhibition.
• Assessed changes in H3K27Ac levels at enhancers and CBP/P300 chromatin occupancy.

Main Results:

• Acute blockade of CBP/P300 bromodomain function led to a specific loss of H3K27Ac from enhancers.
• CBP/P300 protein remained associated with chromatin despite the loss of H3K27Ac.
• Identified a critical role for H3K27Ac in the production of enhancer RNAs (eRNAs).
• Demonstrated the importance of H3K27Ac for the transcription of enhancer-regulated gene networks.

Conclusions:

• H3K27Ac is essential for enhancer function, particularly in eRNA production and the regulation of gene expression networks.
• The CBP/P300 bromodomain plays a critical role in maintaining H3K27Ac at enhancers.
• This study provides new insights into the functional consequences of H3K27Ac loss in hematological malignancies.