陈柱成实验室

The structure of the acetyltransferase NuA4 bound to the nucleosome

    Chemical modifications, such as histone methylation, acetylation, and ubiquitination, directly alter chromatin structure, and/or recruit various downstream reader proteins to regulate gene expression, and are classic epigenetic mechanisms. Histone modifications often coordinate with other regulators to target specific chromatin regions and control specific gene expression. Although histone modifications have been studied extensively, many important questions remain unanswered.

   The N-termini of histone H4 interact with nearby nucleosomes, and play a particularly important role in the formation of high ordered chromatin structure and heterochromatin silencing. NuA4 in yeast and its homolog Tip60 complex in mammalian cells are the key histone acetylation transferases (HATs) that selectively work on nucleosomal H4, which in turn regulate chromatin packaging, and function in transcription activation and DNA repair. Despite the fundamental importance, it remains unclear how the HAT complexes interact with the nucleosome substrate.

    In 2016, we determined the crystal structures of the core catalytic module of NuA4, and the medium-resolution cryoEM structure bound to the nucleosome. The work illustrates a novel position-based, rather than the common sequence-based, mechanism of selective acetylation of the histone tails. In 2022, we determined the high-resolution structure of NuA4 holo-enzyme bound to the nucleosome. Our findings illustrate how NuA4 is assembled, and provide mechanistic insights into nucleosome recognition and transcription coactivation by a histone acetyltransferase. The structure also provides a framework to understand the human homolog complex Tip60.