肿瘤抑制因子ZMYND8参与肿瘤抑制的结构与分子机制研究

锌指-MYND结构域包含蛋白8(ZMYND8)，又叫激活的蛋白激酶C受体7(RACK7)，是含有大约1200个氨基酸残基的表观遗传调控因子，具有异染色质靶向的染色质重塑和转录调控功能。近年来发现ZMYND8是众多关键蛋白复合物，包括染色质重塑及转录因子共调控复合物的核心组分，在肌肉分化、众多癌症和肿瘤的发生、发展过程中发挥转录共抑制、或转录共激活作用。目前ZMYND8及其相关复合物的结构生物学研究未见报道，这阻碍了人们对这一关键表观遗传调控因子作用机制的深入理解和靶向药物的开发。本项目计划以生物大分子晶体学为主要研究手段，与生物物理与生物化学、表观遗传学研究手段相结合，开展ZMYND8蛋白及其与组蛋白、雌激素受体、组蛋白去甲基化酶，以及染色质重塑因子等复合物结构与功能的研究，从分子水平阐明ZMYND8在发育、癌症与肿瘤等疾病发生、发展中的作用机理，为ZMYND8靶向药物的开发奠定基础。

Zinc finger, MYND-containing protein 8 (ZMYND8), also called RACK7 (Receptor for Activated C-kinase 7), is an important epigenetic regulator of ~1,200 amino acids, characteristic of its chromatin remodelling and transcriptional control at heterochromatin loci. Accumulating reports show that ZMYND8 is core component of several critical macromolecular complexes, including chromatin remodelling complexes and transcriptional co-regulator complexes. Moreover, ZMYND8 plays key roles in neural differentiation and development as well as various cancer and tumour cases. However, lack of structural information and molecular mechanisms underlying these important processes hinders our deep understanding of ZMYND8 and development of relevant inhibitors. This project aims to determine the three-dimensional structures of ZMYND8-related complexes, including ZMYND8-H3 histone, ZMYND8-ER，ZMYND8-JARID1d and ZMYND8-GATAD2A complexes to provide molecular insights into ZMYND8 function network in development, cancer and tumours. We expect that our work shall pave the way for development of inhibitors targeting ZMYND8 for therapeutic intervention of those relevant diseases.