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 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to estrogen receptor α (ERα)-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, ERα, 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 ERα-bound enhancers and promoters, which is essential for transcriptional activation. CUT&Tag sequencing for SET and ERα in T47D cells with or without estradiol treatment

SET是一种多功能组蛋白结合型癌蛋白，其调控转录的具体机制尚未阐明。本研究揭示，SET可增强雌激素依赖性转录：敲低SET会完全抑制雌激素应答基因及其增强子RNA（enhancer RNAs, eRNAs）的转录。在17β-雌二醇（17β-estradiol, E2）刺激下，SET可与雌激素受体α（estrogen receptor α, ERα）结合，并被招募至结合了ERα的增强子区域以及雌激素应答元件（estrogen response elements, EREs）处的启动子区域。SET作为组蛋白H2伴侣蛋白（histone H2 chaperone），可通过其酸性C端结构域与H2A.Z动态结合，促进H2A.Z的组蛋白掺入，招募ERα、MLL1与KDM3A，并调控EREs位点的组蛋白甲基化水平。SET缺失会减少凝聚素复合物（condensin complexes）向EREs的招募，并破坏E2依赖性的增强子-启动子环化过程。综上，SET可通过在结合ERα的增强子与启动子区域构建活跃染色质结构，促进E2诱导的基因表达，这一过程对转录激活至关重要。本研究对经或未经雌二醇处理的T47D细胞中的SET与ERα开展了CUT&Tag测序（CUT&Tag sequencing）。