Extremely Long-Range Chromatin Loops Link Topological Domains to Facilitate a Diverse Antibody Repertoire.
Extremely Long-Range Chromatin Loops Link Topological Domains to Facilitate a Diverse Antibody Repertoire.
复制标题
DOI：
10.1016/j.celrep.2015.12.083
复制
发表时间：
2016-02-02
期刊：
影响因子：
8.8
通讯作者：
Kenter AL
中科院分区：
文献类型：
--
作者：
Montefiori L;Wuerffel R;Roqueiro D;Lajoie B;Guo C;Gerasimova T;De S;Wood W;Becker KG;Dekker J;Liang J;Sen R;Kenter AL
早期B细胞发育的特征是在V（D）J重组之前大规模Igh基因座收缩，以促进高度多样性的IG库。然而，对介导位点收缩的分子结构的理解仍然不清楚。我们结合高分辨率染色体构象捕获（3C）技术与三维DNA FISH，以确定三个保守的拓扑结构域。这些拓扑折叠中的每一个都包含一个主要的VH基因家族，其通过Mb级染色质成环在pro-B细胞中并置。转录因子Pax 5组织跨越VHJ 558基因家族的亚结构域。在其不存在下，J558 VH基因不能与近端VH基因相关联，从而为Pax 5缺陷型pro-B细胞中VHJ 558基因重排减少提供了合理的解释。我们认为Igh基因座收缩是几个独立控制的染色质亚结构域的累积效应，这些亚结构域提供了协调最佳抗原受体组装的结构基础设施。
Early B cell development is characterized by large scale Igh locus contraction prior to V(D)J recombination to facilitate a highly diverse Ig repertoire. However, an understanding of the molecular architecture that mediates locus contraction remains unclear. We have combined high resolution chromosome conformation capture (3C) techniques with 3D DNA FISH to identify three conserved topological sub-domains. Each of these topological folds encompasses a major VH gene family that become juxtaposed in pro-B cells via Mb-scale chromatin looping. The transcription factor Pax5 organizes the sub-domain that spans the VHJ558 gene family. In its absence the J558 VH genes fail to associate with the proximal VH genes, thereby providing a plausible explanation for reduced VHJ558 gene rearrangements in Pax5-deficient pro-B cells. We propose that Igh locus contraction is the cumulative effect of several independently controlled chromatin sub-domains that provide the structural infrastructure to coordinate optimal antigen receptor assembly.