Functions of TIP60/NuA4 Complex Subunits in Epigenetic Regulation of Cell Differentiation

The TIP60/NuA4 complex is a very large multifunctional histone acetyltransferase complex of >1.7 megadaltons consisting of 17-20 subunits that plays a pivotal role in epigenetic regulation of numerous cellular processes. It is targeted to the histone H3K4Me3 mark of active transcription by the ING3 epigenetic reader to alter local chromatin structure and transcription. This results in functions as a transcriptional co-activator, a histone dimer exchange factor, cell cycle and apoptosis regulator. In this study we review the effects of altering TIP60 subunit levels or mutational status on chromatin structure and transcriptional activity, and how this impacts different pathways of differentiation across multiple cell types. We focus on the molecular mechanisms by which TIP60/NuA4 contributes to cell fate decisions, focusing on its roles in histone H3 and H4 acetylation by its KAT5 catalytic subunit, chromatin remodeling, and coordination with transcription factors. We also highlight roles of individual TIP60 complex subunits with demonstrated involvement in several forms of differentiation, examining how their distinct functions contribute to lineage specification and developmental transitions. By integrating mechanistic insights with functional outcomes, this review summarizes pathways affected by the TIP60/NuA4 regulator of cellular differentiation and provides perspectives on its potential as a target for modulating cell fate in regenerative medicine.