染色质重塑的功能和机理研究进展  

Functions and mechanisms of chromatin remodelers

作　　者：袁俊杰 陈柱成 Junjie Yuan;Zhucheng Chen(School of Life Sciences,Tsinghua University,Tsinghua-Peking Joint Centre for Life Sciences,Beijing Frontier Research Center for Biological Structure,MOE Key Laboratory of Protein Science,Beijing 100084,China)

机构地区：[1]清华大学生命科学学院,清华-北大生命科学联合中心,清华大学北京生物结构前沿中心,清华大学蛋白质科学教育部重点实验室,北京100084

出　　处：《科学通报》2024年第30期4403-4414,共12页Chinese Science Bulletin

基　　金：国家重点研发计划(2022YFA1302700,2019YFA0508902);国家自然科学基金(32130016,31825016)资助。

摘　　要：染色质重塑蛋白利用ATP的能量改变染色质中核小体的位置和组成,促进组蛋白变体交换、核小体滑动、解聚、或弹出,进而影响基因组DNA可及性.染色质重塑对DNA复制、基因转录和DNA损伤修复等生命过程至关重要.染色质重塑蛋白与一些调控蛋白共同组装形成复杂的分子机器,应答不同的细胞信号,广泛参与细胞分化、组织发育及免疫应答等过程.染色质重塑复合物的功能失调与肿瘤、发育缺陷、神经退行性疾病等众多重大疾病的发生发展密切相关.近年来,有关染色质重塑的机理和作用研究突飞猛进.文章综述了SWI/SNF、ISWI、INO80和CHD四个染色质重塑家族蛋白质复合物的组成和功能特点,阐释了“DNA波”模型这一普适的染色质重塑机制,并总结了染色质重塑活性的多重调控的研究进展,进一步讨论了染色质重塑蛋白对启动子区核小体的调控机理.这些研究对于理解基因表达调控,以及相关疾病的发生发展具有重要意义.Chromatin remodeling is an intricate process that alters the positions and compositions of nucleosomes.It regulates DNA accessibility and gene activity,without changing the underlying DNA sequence.The process is mediated by ATPdependent motor proteins,which exhibit diverse activities,including nucleosome sliding,spacing,ejection,and exchange of histone variants.In eukaryotes,there are a wide spectrum of chromatin remodelers,characterized by a highly conserved ATPase subunit,which often form complex molecular machines with regulatory subunits.They are broadly involved in cell differentiation,tissue development,and immune responses.Dysregulation of chromatin remodeling is implicated in various diseases,including cancers,developmental disorders,and neurodegenerative conditions.Notably,over 20%of cancer patients harbor mutations in genes encoding chromatin remodelers.Certain cancers are even driven exclusively by mutations in chromatin remodelers,highlighting their significance in oncogenesis.Moreover,many types of cancer depend on chromatin remodelers for survival,suggesting chromatin remodelers as promising therapeutic targets for cancer treatment.However,the mechanisms of chromatin remodeling remain enigmatic.Key questions include how chromatin remodelers recognize the nucleosome,how they overcome the extensive histone-DNA interactions to slide the nucleosome,and how they are regulated to achieve diverse activities.Recent advancements in cryo-electron microscopy yield a wealth of highresolution structures of chromatin remodeling complexes.These new studies shed light on the mechanisms of these remodeling enzymes.In this review,we first provide an overview of the compositions of SWI/SNF,ISWI,INO80 and CHD chromatin remodeling families.We then discuss the“DNA wave”model of chromatin remodeling.In short,the two catalytic cores of a remodeling motor bind to nucleosomal DNA and use the energy from ATP binding and hydrolysis to alter the DNAhistone interactions.The DNA is distorted by the motor.Importantly,the DNA d

关 键 词：染色质 核小体 染色质重塑 DNA波 转录调控 肿瘤 

分 类 号：Q343.2[生物学—遗传学]