雷帕霉素诱导β-珠蛋白家族基因座位重塑调控该基因的转换表达  

Rapamycin-inducedβ-Globin Family Locus Remodeling Regulates the Gene Switching Expression

作　　者：许兰 肖亦舒 刘春亚 贾炳豪 杜乐 李冬娜[1] 任立成[1] XU Lan;XIAO Yi-Shu;LIU Chun-Ya;JIA Bing-Hao;DU Le;LI Dong-Na;REN Li-Cheng(Department of Biology,Hainan Medical University,Haikou 571199,China)

机构地区：[1]海南医学院生物学教研室,海口571199

出　　处：《中国生物化学与分子生物学报》2023年第9期1322-1331,共10页Chinese Journal of Biochemistry and Molecular Biology

基　　金：海南省自然科学基金项目(No.820RC638);国家自然科学基金项目(No.31660318);校级研究生创新科研课题(No.HYYS2020-10)资助。

摘　　要：β-珠蛋白基因编码异常导致的β-地中海贫血是许多亚洲国家最常见的血红蛋白病。深入研究珠蛋白基因表达的分子基础和表观遗传机制,是探索治疗地中海贫血新方案的关键。本研究利用FAIRE、3C及ChIP等主要技术方法,探讨雷帕霉素诱导CD4^(+)T细胞核内染色质重塑过程中,β-珠蛋白家族基因座位的三维相互作用网络及其重塑在功能上调控基因表达的分子机制。结果显示,雷帕霉素处理浓度从低到高的变化过程中,珠蛋白基因染色质的开放程度、基因启动子区与调控元件LCR之间的相互作用频率以及CTCF在基因启动子区的富集效率发生不同的改变,这种变化导致了基因表达模式也呈现相同的变化趋势。10 nmol/L浓度处理时,染色质可及性降低,基因表达下降(P<0.05);20 nmol/L和50 nmol/L浓度时,染色质可及性增加,基因表达上调(P<0.05)。本研究通过这种动态的变化过程阐述了β-珠蛋白家族基因表达转换调控的分子机制,为临床精准治疗提供了理论与临床实践基础。β-Thalassemia caused by abnormal coding of theβ-globin gene is the most common hemoglobinopathy in many Asian countries.The in-depth study of the molecular basis and epigenetic mechanism of globin gene expression is the key to explore a new treatment for thalassemia.In this study,FAIRE(formaldehyde-assisted isolation of regulatory elements),3C(chromosome conformation capture)and ChIP(Chromatin Immunoprecipitation)were used to investigate the three-dimensional interaction network ofβ-globin family gene loci and the molecular mechanism of functional regulation of gene expression during rapamycin-induced chromatin remodeling in CD4^(+)T cells.The results showed that the opening degree of globin gene chromatin,the interaction frequency between the gene promoter region and the regulatory element LCR(Locus control regions),and the enrichment efficiency of CTCF(CCCTC-binding factor)in the gene promoter region changed differently during the change of rapamycin treatment concentration from low to high,which led to the same change trend of the gene expression pattern.At the 10nmol/L concentration,chromatin accessibility and gene expression decreased(P<0.05).At 20 nmol/L and 50 nmol/L concentrations,chromatin accessibility increased and gene expression was up-regulated(P<0.05).In this study,the molecular mechanism of gene expression regulation of theβ-globin family was expounded through this dynamic change process.Our work provides a theoretical and clinical prac-tice basis for clinical precision treatment.

关 键 词：β-珠蛋白家族基因 染色质重塑 染色质相互作用 染色质可及性 基因表达调控 

分 类 号：R556.7[医药卫生—血液循环系统疾病]