Functions of TIP60/NuA4 Complex Subunits in Cell Differentiation

Abstract

Highlights: What are the main findings? TIP60/NuA4 functions as an integrated complex—catalytic (TIP60/KAT5), scaffold/ATPase (EP400/EPC1/TRRAP), and reader subunits (ING3, YEATS4, MBTD1, BAF53A/MRG15) cooperate to remodel chromatin during lineage-specific differentiation. Individual subunits have distinct yet convergent roles across neurogenesis, myogenesis, adipogenesis, hematopoiesis, and germ-cell development; viewing the whole complex explains overlapping differentiation phenotypes. What are the implications of the main findings? A whole-complex perspective clarifies why disruption of different subunits yields similar outcomes and helps separate complex-dependent from subunit-specific effects. TIP60/NuA4 emerges as a central epigenetic hub with translational relevance for disorders of development, regeneration, and disease. The TIP60/NuA4 complex is a large, multifunctional histone acetyltransferase assembly of ~1.7 megadaltons, composed of 17–20 subunits, which plays a central role in epigenetic regulation. Through recognition of H3K4me3 by the ING3 reader, TIP60/NuA4 is recruited to sites of active transcription, where it remodels chromatin to regulate gene expression. Its activities include histone acetylation, histone variant exchange, transcriptional co-activation, and regulation of the cell cycle and apoptosis. In this review, we examine how altered subunit levels or mutations impact the chromatin structure and transcriptional activity, and how these changes influence differentiation across diverse cell types. We emphasize the molecular mechanisms by which TIP60/NuA4 shapes lineage specification, including histone H2A and H4 acetylation by the KAT5 catalytic subunit, H2A.Z incorporation by EP400, and interactions with transcription factors such as MyoD, PPARγ, and Myc. By integrating mechanistic and functional insights, we highlight how TIP60/NuA4 acts as a central epigenetic hub in differentiation and contributes to proper developmental transitions.