The SET Oncoprotein Promotes Estrogen-Induced Transcription by Facilitating Establishment of Active Chromatin

SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here, we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs (eRNAs). In response to 17ß-estradiol (E2), SET binds to the estrogen receptor a (ERa) and is recruited to estrogen receptor a (ERa)-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERa, MLL1 and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERa-bound enhancers and promoters, which is essential for transcriptional activation. Overall design: CUT&Tag sequencing for SET and ERa in T47D cells with or without estradiol treatment