B cell development

B淋巴细胞通过抗体识别并消灭病毒和细菌。当B细胞遇到并识别病原体表面的外来物质时，这些分子在免疫反应中分泌。然而，B细胞是如何被激活的还没有完全解决。控制这种激活的一个关键机制是转录，即基因表达的过程。B细胞发育过程中的转录是由启动子序列和多种远端顺式调控元件协调的。其中的关键是增强子，它与启动子结合，以组织特异性的方式增加靶基因的转录输出。增强子与非调节性DNA的典型区别在于它们对DNA酶消化的超敏感性，以及与称为染色质修饰剂的特定蛋白质的结合。基于这些参数，最近发现了40万个显示增强子样特征的基因组位点，覆盖了近10%的人类基因组。

B lymphocytes recognize and destroy viruses and bacteria though antibodies. These molecules are secreted during the immune response, when B cells encounter and recognize foreign material on the surface of pathogens. How B cells are activated however is not entirely resolved. One key mechanism that controls this activation is transcription, the process whereby genes are expressed. Transcription during B cell development is orchestrated by promoter sequences and a variety of distal cis-regulatory elements. Key among these are enhancers, which associate with promoters to increase the transcriptional output of target genes in a tissue-specific manner. Enhancers are typically distinguished from non-regulatory DNA by their hypersensitivity to digestion with DNAses, and binding of specific proteins known as chromatin modifiers. Based on these parameters, 400,000 genomic sites displaying enhancer-like features were recently discovered, spanning nearly 10% of the human genome. Enhancers control cell identity by recruiting transcription factors, cofactors, and RNA Polymerase II, the enzyme that mediates transcription. All of these proteins mediate promoter-enhancer interactions by looping out of intervening sequences. In contrast to promoters and insulators, which vary little across cell types, the enhancer landscape changes considerably during development. This feature predicts that functional 3D connectivity in mammalian cells i) must display a high degree of tissue specificity and ii) should closely reflect transcriptome changes during cell differentiation. However, these ideas have not been fully explored because of the difficulty of mapping promoter-enhancer connections during development. In the absence of direct approaches, enhancers have been typically assigned to cognate promoters based on linear proximity or shared chromatin states. This strategy has limitations because enhancers do not always regulate nor share chromatin profiles with the nearest promoter. To overcome this challenge, this past year we applied a recently developed protocol (ChIA-PET) that permits visualization of promoter-enhancers interactions. In a manuscript published in Cell (Kieffer-Kwon et al, we mapped these interactions in mouse stem cells and B lymphocytes. We compared and contrasted these interactome maps and discovered several very interesting features: 1- We confirmed that enhancer usage varies widely across tissues. 2- Unexpectedly, we find that this feature extends not only to genes only expressed in stem cells or B cells, but also on those expressed ubiquitously (the so called housekeeping genes). 3- By means of genomic techniques we showed that these changing enhancers recruit cell-specific factors. These findings are important because they showed that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner. Because mutations that cause diseases such as lupus and arthritis occur at enhancer elements, our techniques to map these domains and their interactions in a genome-wide manner will be highly valuable to those studying autoimmune and other disorders.