Novel Coregulators of Estrogen Receptor in Enhancer-regulated Transcription

雌激素（E2或17 b-雌二醇）及其核受体ERα对包括乳腺在内的多个器官的正常发育和疾病状态至关重要。E2和ERα主要通过结合远端增强子来调节这些生物学背景下的转录程序。越来越多的证据表明，ERα结合增强子的功能失调深刻地改变了正常的转录程序，导致发育缺陷、疾病和激素抵抗。然而，增强子功能/功能障碍的分子机制在很大程度上是未知的。 本实验室一直致力于研究ERα结合增强子的两个关键问题：1）雌激素调节增强子在不同条件下是如何组装的？2)增强子组分如何在体内编码每个单独增强子的环境特异性功能？利用一种强大的邻近蛋白质组学方法，我们最近发现了额外的ERα相互作用的辅助调节因子，包括雅普/TEAD，这是Hippo通路中介导核效应的两个关键组分。我们的初步数据表明，雅普/TEAD以非经典的方式与ERα结合增强子上的ERα相互作用，并在正常信号条件下或在激素抵抗的发展过程中在ERα介导的转录程序中发挥关键作用。在这份拨款申请中，我们提出了两个具体的目标来检验雅普/TEAD是否重要的假设 ERα结合增强子激活所需的新的辅助调节因子，以及雅普/TEAD和ERα之间的协同相互作用通过增强子重编程控制ERα结合增强子在体内的特异性功能。本研究将为阐明雅普/TEAD和ERα信号通路在不同条件下如何在染色质水平上发生交叉并汇聚于增强子上调控下游基因表达提供机制解释，为进一步开发ER靶向治疗奠定基础。

Novel Coregulators of Estrogen Receptor in Enhancer-regulated Transcription Estrogen (E2 or 17b-estradiol) and its nuclear receptor ERα are critical for the normal development and disease conditions of multiple organs, including mammary glands. E2 and ERα regulate transcriptional programs in these biological contexts through binding primarily at distal enhancers. Increasing evidence indicates that functional dysregulation of ERα-bound enhancers profoundly alters normal transcriptional programs, leading to developmental defects, diseases, and hormone resistance. However, the molecular mechanisms underlying the enhancer function/dysfunction are largely unknown. My lab has been focusing on studying two key questions on ERα-bound enhancers: 1) how are estrogen-regulated enhancers assembled under different conditions? 2) how do the enhancer components encode the context-specific function of each individual enhancer in vivo? Using a powerful proximity proteomics approach, we recently identified additional ERα-interacting coregulators including YAP/TEAD, two key components of Hippo pathway to mediate nuclear effects. Our preliminary data suggest YAP/TEAD function in a non-canonical manner to interact with ERα on ERα-bound enhancers and play a key role in ERα-mediated transcriptional programs under normal signaling condition or during the development of hormone resistance . In this grant proposal, we are proposing two specific aims to test the hypothesis that YAP/TEAD are important novel coregulators required for the activation of ERα-bound enhancers, and the cooperative interactions between YAP/TEAD and ERα control the context-specific function of ERα-bound enhancers in vivo through enhancer reprogramming. The proposed work will provide a mechanistic interpretation on how YAP/TEAD and ERα signaling crosstalk at the chromatin level and converge on enhancers to control downstream gene expression under different conditions, and lay the foundation for future development of improved ER-targeted therapy.