Recruitment of the cofactor p300: Three Non-Exclusive Mechanisms for Chromatin Targeting

Abstract

Dynamic transcriptional control is critical for cell identity and adaptive responses, and dysregulation contributes to many diseases, including cancer. The key cofactor E1A-associated protein p300, a lysine acetyltransferase (KAT3 family), is central to enhancer activation and modulates the activity of over 400 transcription factors (TFs) and regulatory proteins. Because p300 lacks an intrinsic DNA-binding domain, the question of how it is precisely moved towards specific chromatin sites to regulate and sustain transcription remains unsolved. This review integrates evidence supporting three non-exclusive mechanisms proposed for p300 chromatin recruitment. These mechanisms are based on p300 structural elements, which include TF-interaction domains (TFIDs), nucleosome-interacting domains, and long intrinsically disordered regions (IDRs). TF-mediated anchoring (Model 1) establishes initial specificity, where clusters of TFs on dense enhancer motifs cooperatively bind p300 TFIDs. The nucleosome-interacting domains (Model 2) provide stabilisation. The bromodomain (BRD) reads pre-existing acetyl marks (such as H4ac) and positions the catalytic domain to write H3K27ac, creating a feed-forward loop that strengthens enhancer activation. Lastly, IDR-IDR mediated co-condensation (Model 3) allows p300, which is about 60% disordered, to co-localise with disordered TF activation domains, forming biomolecular condensates. These condensates increase the local concentration and encounter frequency of interaction partners, thereby amplifying both TFID docking (Model 1) and nucleosome engagement (Model 2). This review proposes that p300 recruitment is a multi-step and context-dependent process that combines all three Models. TF clusters initiate the recruitment, nucleosome contacts hold the position and help the enzyme write acetylation marks, and condensation amplifies these effects. Understanding these cooperative recruitment routes offers therapeutic targets. Modulating p300 recruitment, for example, by using selective BRD inhibitors, offers a therapeutic strategy to specifically disrupt gene networks occupied by disease-critical TFs with reduced genome-wide side effects.