Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation.
Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation.
复制标题
拓扑相关结构域描绘了对体细胞超突变的易感性。
DOI：
10.1016/j.celrep.2019.11.039
复制
发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Schatz,DavidG
中科院分区：
文献类型：
--
作者：
Senigl,Filip;Maman,Yaakov;Dinesh,RaviK;Alinikula,Jukka;Seth,RashuB;Pecnova,Lubomira;Omer,ArinaD;Rao,SuhasSP;Weisz,David;Buerstedde,Jean-Marie;Aiden,ErezLieberman;Casellas,Rafael;Hejnar,Jiri;Schatz,DavidG
体细胞超突变（SHM）将点突变引入免疫球蛋白（IG）基因，但也引起基因组其他部分的突变。我们已经使用慢病毒SHM报告载体来鉴定对SHM敏感（“热”）和抗性（“冷”）的基因组区域，揭示了SHM敏感性和抗性通常是整个拓扑相关结构域（TADs）的性质。热和冷TAD的比较揭示，虽然转录水平是相等的，但热TAD富集了粘附素加载器NIPBL、超级增强子、暂停/停滞的RNA聚合酶2的标记物和多种重要的B细胞转录因子。我们证明，至少有一些热的TADs包含增强子，具有SHM靶向活性，并插入一个强大的IgSHM靶向元素到一个冷的TADs使其热。我们的研究结果导致一个模型的SHM易感性涉及合作行动ofcis-acting SHM靶向元素和动态和建筑性能的TADs。
Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible ("hot") and resistant ("cold") to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strongIgSHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action ofcis-acting SHM targeting elements and the dynamic and architectural properties of TADs.