Which chromatin modifications regulate the initiation of V(D)J recombination?

为了能够对抗大量的潜在感染，我们需要生产一套高度多样化的抗体和T细胞受体分子。需要数百万个抗体，如果每个细胞都携带一个不同的基因来编码这些抗体，那么将需要数千兆碱基的DNA。相反，抗体基因是通过称为V（D）J重组的过程从单个基因片段重新组装的：一个基因片段是从一个巨大的库中随机选择的，并与来自另一个库的基因片段连接。大量的不同组合导致了大量的抗体基因。虽然这种策略有其优点，但它也带来了危险：DNA必须被破坏和重新连接，在这个过程中的错误可能导致错误的DNA片段被重新连接。在最极端的情况下，来自不同染色体的DNA连接在一起，导致染色体易位。后者是白血病和淋巴瘤的主要原因。这项研究旨在了解V（D）J重组在正常个体中是如何调节的，然后了解错误如何导致白血病和淋巴瘤。更具体地说，它旨在确定DNA断裂是如何靶向的。这些知识将使我们能够确定哪些环境因素会增加基因组中不适当位点断裂的风险，从而引发白血病和淋巴瘤。迄今为止，我们知道必须使序列易于切割：细胞核中的DNA以高度包装的结构存在，称为染色质;这保护DNA免于重组的开始。然而，响应于适当的信号，这种染色质包装被特异性地解开以允许重组发生。被称为增强子的序列被认为在控制染色质解包装方面很重要;它们调节通过重组中使用的基因片段的转录。转录通过修饰包装蛋白导致染色质的物理变化。该项目旨在了解转录本身、其诱导的修饰或增强子诱导的修饰是否在重组的初始阶段靶向DNA断裂。一旦靶向DNA断裂的修饰已知，我们将能够确定哪些因素增加了基因组不适当区域发生DNA断裂的风险，从而更好地了解白血病和淋巴瘤的风险因素。

To be able to combat a vast number of potential infections, we need to produce a highly diverse set of antibody and T cell receptor molecules. Millions of antibodies are needed and if every cell carried a distinct gene to encode each of these antibodies, thousands of megabases of DNA would be required. Instead, antibody genes are assembled de novo from individual gene segments by a process known as V(D)J recombination: One gene segment is randomly chosen from a vast pool and joined to a gene segment from a separate pool. The huge number of different combinations results in an enormous number of antibody genes. Although this strategy has its advantages, it also carries dangers: DNA must be broken and rejoined and mistakes in this process can result in the wrong pieces of DNA being rejoined. In the most extreme cases, DNA from different chromosomes becomes joined, resulting in a chromosome translocation. The latter are a major cause of leukaemias and lymphomas. This research aims to understand how V(D)J recombination is regulated in normal individuals to then understand how mistakes lead to leukaemias and lymphomas. More specifically, it aims to determine how the DNA breaks are targeted. This knowledge will then enable us to determine which environmental factors increase the risk of breaks at inappropriate sites in the genome that can trigger leukaemias and lymphomas.To date, we know that sequences must be made accessible for them to be cut: DNA in the nucleus exists in a highly packaged structure, known as chromatin; this protects DNA from the initiation of recombination. However, in response to the appropriate signals, this chromatin packaging is specifically unravelled to allow recombination to occur. Sequences, known as enhancers, are thought to be important in controlling chromatin unpackaging; they regulate transcription that passes through the gene segments used in recombination. Transcription results in physical changes in chromatin by modifying the packaging proteins. This project aims to understand whether transcription itself, the modifications that it induces, or the modifications induced by enhancers target DNA breaks for the initial stages of recombination. Once the modifications that target DNA breaks are known, we will be able to determine which factors increase the risk of DNA breaks occurring in inappropriate regions of the genome and thus gain a better insight into the risk factors for leukaemias and lymphomas.