Structural insights into the human NuA4/TIP60 acetyltransferase and chromatin remodeling complex

Area of Science:

• Molecular Biology
• Epigenetics
• Structural Biology

Background:

• The NuA4/TIP60 complex acetylates histones and incorporates H2A.Z, regulating gene expression and genome stability.
• This complex is a fusion of yeast SWR1 and NuA4 complexes, highlighting its evolutionary significance.

Purpose of the Study:

• To elucidate the structural organization of the NuA4/TIP60 complex.
• To understand the role of the EP400 subunit in complex assembly and function.
• To investigate the impact of TRRAP subunit loss on complex localization and histone modification.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structure of the NuA4/TIP60 complex.
• Biochemical assays were used to analyze subunit interactions and complex formation.
• Genome-wide analyses were performed to assess the distribution and acetylation of H2A.Z.

Main Results:

• Cryo-EM revealed that the EP400 subunit acts as a scaffold, organizing functional modules including the ARP module.
• EP400 binding to TRRAP prevents interaction with the SAGA complex, inhibiting hybrid complex formation.
• Loss of TRRAP resulted in NuA4/TIP60 mislocalization and altered H2A.Z distribution and acetylation across the genome.

Conclusions:

• The EP400 subunit is critical for the structural integrity and specific arrangement of the NuA4/TIP60 complex.
• TRRAP's role in localization is essential for the proper function of NuA4/TIP60 in H2A.Z deposition and acetylation.
• NuA4/TIP60 functions as a single macromolecular assembly with dual roles in gene regulation and genome stability.