The SAGA continues: The rise of cis- and trans-histone crosstalk pathways

Fueled by key technological innovations during the last several decades, chromatin-based research has greatly advanced our mechanistic understanding of how genes are regulated by epigenetic factors and their associated histone-modifying activities. Most notably, the landmark finding that linked histone acetylation by Gcn5 of the Spt–Ada–Gcn5–acetyltransferase (SAGA) complex to gene activation ushered in a new area of chromatin research and a realization that histone-modifying activities have integral genome functions. This review will discuss past and recent studies that have shaped our understanding of how the histone-modifying activities of SAGA are regulated by, and modulate the outcomes of, other histone modifications during gene transcription. Because much of our understanding of SAGA was established with budding yeast, we will focus on yeast as a model. We discuss the actions of cis- and trans-histone crosstalk pathways that involve the histone acetyltransferase, deubiquitylase, and reader domains of SAGA. We conclude by considering unanswered questions about SAGA and related complexes. •Discusses advances in understanding SAGA regulation of transcription via histone post-translational modifications (PTMs).•Discusses the functions of the HAT and DUB modules of SAGA in establishing, and regulating, histone PTMs.•Discusses the activities of histone crosstalk pathways and how reader domains promote feedforward and feedback loops.