The 3D-Structure of the Immunoglobulin Heavy Chain Locus

免疫球蛋白重链基因座的 3D 结构

• 批准号: 8788490
• 负责人: CORNELIS MURRE
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788490
• 关键词: Adopted; Alleles; Antibody Diversity; Antigen Receptors; Antigens; B-Cell Development; B-Lymphocytes; Beryllium; Binding; Binding Sites; Cell Culture Techniques; Cells; Chromatin; Chromatin Fiber; Chromosomes; Code; Complex; Computer Simulation; Data; Development; Diffusion; Disease; Distal; Elements; Fiber; Frequencies; Gene Rearrangement; Generations; Genome; Genomics; Geometry; Goals; Health; Heavy-Chain Immunoglobulins; IGH@ gene cluster; Image; Immune response; Indium; Individual; Insulator Elements; Interphase; Invaded; Measurement; Molecular Conformation; Monitor; Motion; Mus; Names; Nature; Ocular orbit; Pattern; Play; Population; Process; Property; Radial; Receptor Gene; Research; Resolution; Site; Structure; Testing; Three-dimensional analysis; Time; Virus; base; insight; pathogen; progenitor; recombinase; three dimensional structure

DESCRIPTION (provided by applicant): The goal of the research proposed in this application is to explore the mechanisms that underpin antigen receptor gene rearrangement. The antigen receptor loci are organized in distinct domains that contain multiple variable (VH), diversity (DH) joining (JH) and constant (CH) coding elements. To probe the topography of the Igh locus, we as well as others, have determined the spatial distances separating genomic markers that span the entire locus. The spatial distance measurements were compared to computer simulations of distinct chromatin topologies. These studies predicted that the Igh locus is structured into domains consisting of clusters of loops. Using computational geometric approaches we showed that the Igh locus is organized as individual domains that merge upon commitment to the B cell fate. More recent observations have identified potential anchors, proposed to sequester the proximal variable coding elements to lie in orbit at the base of a rosette, surrounding the DHJH coding element complexed to the recombinase. Taken together, these studies have suggested that during early B cell development, the entire repertoire of VH regions (2.5 Mbp) is merged and juxtaposed to the DH elements, allowing the VH regions to encounter DHJH coding elements with relatively high and similar frequencies. Here we propose to continue these studies and determine the spectrum of 3D-conformations of the Igh locus adopted by the Igh locus fiber during the developmental progression of B cell progenitors. We would describe at high resolution the trajectories adopted by the Igh locus in interphase chromatin. We would examine how the topology of the Igh locus fiber is regulated during developmental progression. We would examine how VH regions separated by large genomic distances have equal opportunities to encounter DHJH elements in developing B cell progenitors. In summary, these studies would provide mechanistic insight into how antibody diversity is generated.

描述（由申请人提供）：本申请中提出的研究的目的是探索抗原受体基因重排的机制。抗原受体基因座在包含多个变量（VH），多样性（DH）连接（JH）和常数（CH）编码元件的不同域中组织。为了探测IGH基因座的地形，我们和其他人都确定了跨整个基因座的基因组标记的空间距离。将空间距离测量与对不同染色质拓扑的计算机模拟进行了比较。这些研究预测，IGH基因座是由循环簇组成的域。使用计算几何方法，我们表明IGH基因座是在对B细胞命运承诺后合并的单个领域。最新的观察结果已经确定了潜在的锚点，该锚点是为了隔离近端变量编码元件，以位于玫瑰花结束的轨道，周围围绕着与重组酶复杂化的DHJH编码元件。综上所述，这些研究表明，在B细胞早期的发展中，VH区域（2.5 Mbp）的整个曲目合并并并置与DH元素并置，从而使VH区域遇到相对较高和相似频率的DHJH编码元件。在这里，我们建议继续这些研究，并确定B细胞祖细胞发育进展过程中IGH基因座纤维采用的IGH基因座的3D构造的频谱。我们将在高分辨率上描述IGH基因座相间染色质中采用的轨迹。我们将研究在发育进展过程中如何调节IGH基因座纤维的拓扑。我们将研究如何在开发B细胞祖细胞中遇到DHJH元素的较大基因组距离分离的VH区域如何。总而言之，这些研究将提供有关如何产生抗体多样性的机械洞察力。