BRD4 binds the nucleosome via both histone and DNA interactions

Area of Science:

• Molecular Biology
• Epigenetics
• Structural Biology

Background:

• BRD4 (bromodomain and extraterminal) proteins are key transcriptional regulators.
• BRD4 is recruited to chromatin by binding acetylated histone tails via its bromodomains (BD1 and BD2).
• Previous studies focused on individual bromodomain interactions, not the full-length protein with nucleosomes.

Purpose of the Study:

• To elucidate the structural mechanism of full-length BRD4 binding to nucleosomes.
• To investigate the role of histone acetylation in BRD4-nucleosome interactions.
• To identify novel nucleosome binding mechanisms of BRD4.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of BRD4 short (BRD4-S) bound to a nucleosome.
• Biochemical assays to study BRD4 binding to nucleosomes with and without histone acetylation.

Main Results:

• The cryo-EM structure reveals BRD4 BD1 engages both histone H4 tail and nucleosomal DNA.
• BRD4 BD1 presents the acetylated H4 tail for potential interactions with other chromatin proteins.
• Biochemical studies show BRD4 binds nucleosomes tightly even without histone acetylation, utilizing regions outside its bromodomains.
• Histone H4 acetylation influences the conformation of the BRD4/nucleosome complex.

Conclusions:

• BRD4 employs a dual mechanism for nucleosome binding, involving bromodomain interactions and acetylation-independent binding.
• The structure provides insights into BRD4's role in chromatin regulation and potential therapeutic targeting.
• Histone acetylation modulates BRD4's interaction with the nucleosome, affecting complex conformation.