Structural basis for acetylated histone H4 recognition by the human BRD2 bromodomain

Area of Science:

• Epigenetics and Molecular Biology
• Structural Biology
• Chromatin Biology

Background:

• Bromodomains and extra-terminal domain (BET) proteins bind acetylated chromatin, regulating transcription and viral genome integration.
• BRD2, a BET family member, interacts with acetylated chromatin during mitosis to promote transcriptional activation.

Purpose of the Study:

• To determine the structural basis of BRD2's recognition of acetylated histone H4 tails.
• To elucidate the role of specific lysine residues in histone H4 acetylation in BRD2 binding.

Main Methods:

• X-ray crystallography was used to obtain the structures of the human BRD2 N-terminal bromodomain (BRD2-BD1) complexed with Lys-12-acetylated H4 peptides.
• Binding studies were performed to identify key residues involved in the interaction.
• Mutagenesis was employed to assess the functional significance of specific lysine residues.

Main Results:

• The crystal structures reveal how BRD2-BD1 recognizes H4 peptides acetylated at Lys-12 (H4K12ac).
• Hypoacetylated Lys-8 of H4 binds within a cavity at the BRD2-BD1 dimer interface.
• Residues within BRD2-BD1 responsible for H4K12ac recognition were identified.
• Mutation of Lys-8 in H4K12ac peptides significantly reduced binding to BRD2-BD1, highlighting Lys-8's critical role.

Conclusions:

• These findings provide a structural framework for understanding how BET bromodomains interpret the histone code.
• The recognition of a longer segment of the histone H4 tail by BRD2-BD1 may prevent histone code erasure during the cell cycle.
• This structural insight is crucial for understanding epigenetic regulation and potential therapeutic targeting of BET proteins.