HSP70精氨酸甲基化在雌激素靶基因转录调控中的作用

China is one of the fastest growth country in breast cancer incidence, so strengthening basic researches in molecular mechanisms of the development of breast cancer accords with national health needs. One of the effective means of solving this problem is precisely exploring the role of the molecular mechanisms which involved in transcription activating estrogen target genes. Our previous studies found that CARM1/PRMT4 arginine-methylated the site 469 of heat shock protein 70, HSP70 R469me1 highly and specifically expressed in breast cancer clinical samples and HSP70 was required for estrogen target genes transcription activating. How does HSP70 R469me1 mediated by CARM1/PRMT4 regulate the target genes of estrogen and its role in the development of breast cancer will be the research emphasis in the project. This project will address the following issues: 1) Testing the role of the HSP70 R469me1 and CARM1/PRMT4 by cells and animal model in regulating the development of breast cancer. 2) Determinng the the genome specific location and distribution of HSP70 R469me1 and CARM1/PRMT4 in breast cancer cells through chromatin immunoprecipitation combining with high throughput sequencing (CHIP-seq), thus inferring the mechanism of the spatial pattern; 3) Comprehensively detecting of HSP70 R469me1 and CARM1/PRMT4 on the influence degree and way of the estrogen target gene transcription by Global run-on combining with high throughput sequencing (Gro-seq); 4) Screening active small molecule targeting CARM1/PRMT4 which specifically regulates HSP70 R469me1 through the in vitro, cell and animal experimental to detect its specificity and efficiency. Collectively, the project will uncover a mechanism by which HSP70 is activated by arginine methylation to regulate estrogen target genes that enhance breast cancer progression.

中国是乳腺癌发病率增长最快的国家之一，加强乳腺癌发生发展分子机制的研究，符合国家健康需求。解决这一问题的有效手段之一就在于精确地阐述参与雌激素靶基因激活的调控因子的作用机制。我们发现CARM1/PRMT4介导的HSP70 R469me1在乳腺癌样品中高度特异性表达，HSP70也参与调控雌激素的靶基因。HSP70如何通过其新的活性调控方式（精氨酸甲基化）调节雌激素靶基因还不清楚。我们将通过CHIP-seq和Gro-seq全面地检测分析HSP70 R469me1、CARM1/PRMT4对雌激素靶基因转录的调控，探讨潜在的分子作用机制并阐述两者在乳腺癌发生发展中的作用，筛选特异调控HSP70 R469me1的CARM1/PRMT4的小分子抑制剂，以期达到抑制乳腺癌生长的目的。

中国是乳腺癌发病率增长最快的国家之一，加强乳腺癌发生发展分子机制的研究，符合国家健康需求。解决这一问题的有效手段之一就在于精确地阐述参与雌激素靶基因激活的调控因子的作用机制。我们发现CARM1介导的HSP70 R469me1在乳腺癌样品中高度特异性表达，HSP70也参与调控雌激素的靶基因。HSP70通过其新的活性调控方式（精氨酸甲基化）调节雌激素靶基因。我们通过CHIP-seq和RNA-seq全面地检测分析了HSP70，CARM1对雌激素靶基因转录的调控。探讨了分子作用机制并阐述了两者在乳腺癌发生发展中的作用，为筛选特异调控CARM1的小分子抑制剂，以期达到抑制乳腺癌生长的目的奠定了理论基础。