College of Life Science and Technology, Xinjiang University, Urumqi 830000, China.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2023 Feb 21;120(8):e2206878120. doi: 10.1073/pnas.2206878120. Epub 2023 Feb 15.
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. In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to 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.
SET 是一种多功能的组蛋白结合致癌蛋白，其通过一种不明确的机制调节转录。在这里，我们发现 SET 增强了雌激素依赖性转录。SET 敲低会阻断雌激素反应基因及其增强子 RNA 的转录。在 17β-雌二醇（E2）的刺激下，SET 与雌激素受体 α（ERα）结合，并被募集到雌激素反应元件（EREs）处 ERα 结合的增强子和启动子上。SET 作为一种组蛋白 H2 伴侣，通过其酸性 C 端结构域与 H2A.Z 动态结合，并促进 H2A.Z 的掺入、ERα、MLL1 和 KDM3A 的加载，并调节 EREs 处的组蛋白甲基化。SET 缺失会减少凝聚酶复合物在 ERE 处的募集，并损害 E2 依赖的增强子-启动子环化。因此，SET 通过在 ERα 结合的增强子和启动子上建立活跃的染色质结构，来促进 E2 诱导的基因表达，这对于转录激活是必不可少的。
