CARM1通过甲基化染色质重塑复合物NuRD调控基因转录促进乳腺癌发生发展的功能与分子机制研究

乳腺癌是全球女性人群中最常见且致死率最高的癌症，而中国又是乳腺癌发病率增长最快的国家之一。项目申请人前期研究成果发现表观遗传调控子CARM1在乳腺癌中高表达且高表达预后差，但是其具体分子机制并不清楚。因此，本项目进一步通过亲和纯化-质谱分析系统性地鉴定CARM1相互作用蛋白组学，并从中筛选出与CARM1相互作用的NuRD复合物，并通过转录组学、基因编辑技术、染色质免疫共沉淀技术、蛋白质组学以及其他细胞和动物模型的肿瘤生物学等多种手段和技术联合使用，深入阐述CARM1-NuRD复合物在乳腺癌中发生发展中的分子机制，确立一条以CARM1-NuRD复合物-乳腺癌发生发展的分子通道，揭示乳腺癌新的药物靶点，为乳腺癌的防治提供新的策略。

Breast cancer has the highest morbidity and mortality among women worldwide, and the number of reported cases of breast cancer has increased dramatically in China in recent years. Our previous study found that the epigenetic regulator CARM1, an arginine methyltransferase, is highly expressed in breast cancer and correlated with poor prognosis. However, the underlying molecular mechanisms how CARM1 contributes to breast carcinogenesis remain unclear. Our preliminary results showed that CARM1 interacts with the chromatin remodeling complex NuRD through large-scale affinity purification followed by high resolution tandem mass spectrometry (AP-MS/MS). In this proposal, we will combine RNA-seq, ChIP-seq, CRISPR gene editing, proteomics analysis, and other cellular and animal models for tumor biology to further explore the function and molecular mechanism of CARM1 in breast carcinogenesis, establishing a regulatory axis composed of CARM1, NuRD complex, gene transcription and breast carcinogenesis. We aim to provide insights into how CARM1 contributes to breast cancer, and reveal new drug targets for the prevention and treatment of breast cancer.