• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

两种相互排斥的局部染色质状态驱动高效的V(D)J重组。

Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination.

作者信息

Bolland Daniel J, Koohy Hashem, Wood Andrew L, Matheson Louise S, Krueger Felix, Stubbington Michael J T, Baizan-Edge Amanda, Chovanec Peter, Stubbs Bryony A, Tabbada Kristina, Andrews Simon R, Spivakov Mikhail, Corcoran Anne E

机构信息

Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.

Bioinformatics Group, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.

出版信息

Cell Rep. 2016 Jun 14;15(11):2475-87. doi: 10.1016/j.celrep.2016.05.020. Epub 2016 Jun 2.

DOI:10.1016/j.celrep.2016.05.020
PMID:27264181
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4914699/
Abstract

Variable (V), diversity (D), and joining (J) (V(D)J) recombination is the first determinant of antigen receptor diversity. Understanding how recombination is regulated requires a comprehensive, unbiased readout of V gene usage. We have developed VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products. We reveal a 200-fold range of recombination efficiency among recombining V genes in the primary mouse Igh repertoire. We used machine learning to integrate these data with local chromatin profiles to identify combinatorial patterns of epigenetic features that associate with active VH gene recombination. These features localize downstream of VH genes and are excised by recombination, revealing a class of cis-regulatory element that governs recombination, distinct from expression. We detect two mutually exclusive chromatin signatures at these elements, characterized by CTCF/RAD21 and PAX5/IRF4, which segregate with the evolutionary history of associated VH genes. Thus, local chromatin signatures downstream of VH genes provide an essential layer of regulation that determines recombination efficiency.

摘要

可变（V）、多样（D）和连接（J）（V（D）J）重组是抗原受体多样性的首要决定因素。要理解重组是如何被调控的，需要对V基因的使用情况进行全面、无偏差的读出。我们开发了VDJ测序（VDJ-seq），这是一种基于DNA的新一代测序技术，可对重组产物进行定量分析。我们揭示了在原代小鼠Igh基因库中，重组V基因之间的重组效率范围达200倍。我们利用机器学习将这些数据与局部染色质图谱整合，以识别与活跃的VH基因重组相关的表观遗传特征的组合模式。这些特征位于VH基因下游，并在重组过程中被切除，揭示了一类不同于表达调控的、控制重组的顺式调控元件。我们在这些元件上检测到两种相互排斥的染色质特征，其特征分别为CTCF/RAD21和PAX5/IRF4，它们与相关VH基因的进化历史相关。因此，VH基因下游的局部染色质特征提供了决定重组效率的关键调控层面。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/a707126254a6/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/d11b4da3e529/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/ceba44831996/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/bebaf40dcfd9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/f3c53c62347b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/b71296cafbc5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/56463074d4df/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/26ea130ebc2a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/a707126254a6/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/d11b4da3e529/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/ceba44831996/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/bebaf40dcfd9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/f3c53c62347b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/b71296cafbc5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/56463074d4df/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/26ea130ebc2a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c9e0/4914699/a707126254a6/gr7.jpg

相似文献

1
Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination.两种相互排斥的局部染色质状态驱动高效的V(D)J重组。
Cell Rep. 2016 Jun 14;15(11):2475-87. doi: 10.1016/j.celrep.2016.05.020. Epub 2016 Jun 2.
2
Insertion of an imprinted insulator into the IgH locus reveals developmentally regulated, transcription-dependent control of V(D)J recombination.将印记绝缘子插入免疫球蛋白重链（IgH）基因座揭示了V（D）J重组的发育调控、转录依赖性控制。
Mol Cell Biol. 2015 Feb;35(3):529-43. doi: 10.1128/MCB.00235-14. Epub 2014 Nov 17.
3
Local Chromatin Features Including PU.1 and IKAROS Binding and H3K4 Methylation Shape the Repertoire of Immunoglobulin Kappa Genes Chosen for V(D)J Recombination.包括PU.1和IKAROS结合以及H3K4甲基化在内的局部染色质特征塑造了用于V(D)J重组的免疫球蛋白κ基因的 repertoire。 （这里“repertoire”在免疫学语境下准确含义较难简单直译，可意译为“库”等，具体结合上下文确定准确表述，整体先按原文翻译保留该词）
Front Immunol. 2017 Nov 17;8:1550. doi: 10.3389/fimmu.2017.01550. eCollection 2017.
4
Molecular basis for differential Igk versus Igh V(D)J joining mechanisms.Igk 与 Igh V(D)J 连接机制差异的分子基础。
Nature. 2024 Jun;630(8015):189-197. doi: 10.1038/s41586-024-07477-y. Epub 2024 May 29.
5
Control of antigen receptor diversity through spatial regulation of V(D)J recombination.通过V(D)J重组的空间调控来控制抗原受体多样性。
Cold Spring Harb Symp Quant Biol. 2013;78:11-21. doi: 10.1101/sqb.2013.78.019943. Epub 2014 Feb 28.
6
Epigenetic modifications of the V region after DJ recombination in Pro-B cells.前B细胞中DJ重排后V区的表观遗传修饰。
Immunology. 2017 Oct;152(2):218-231. doi: 10.1111/imm.12758. Epub 2017 Jun 23.
7
Contribution of the IGCR1 regulatory element and the 3' CTCF-binding elements to regulation of V(D)J recombination.IGCR1 调控元件和 3' CTCF 结合元件对 V(D)J 重组的调控作用。
Proc Natl Acad Sci U S A. 2023 Jun 27;120(26):e2306564120. doi: 10.1073/pnas.2306564120. Epub 2023 Jun 20.
8
Spatial Regulation of V-(D)J Recombination at Antigen Receptor Loci.抗原受体基因座处V-(D)J重组的空间调控
Adv Immunol. 2015;128:93-121. doi: 10.1016/bs.ai.2015.07.006. Epub 2015 Aug 13.
9
Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination.受调控的大规模核小体密度模式和精确的核小体定位与V(D)J重组相关。
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6427-E6436. doi: 10.1073/pnas.1605543113. Epub 2016 Oct 3.
10
CTCF-Binding Elements Mediate Accessibility of RAG Substrates During Chromatin Scanning.CTCF 结合元件介导染色质扫描过程中 RAG 底物的可及性。
Cell. 2018 Jun 28;174(1):102-116.e14. doi: 10.1016/j.cell.2018.04.035. Epub 2018 May 24.

引用本文的文献

1
VH-replacement shapes the antibody repertoire by removing the genes of non-functional heavy-chains.VH 替换通过去除无功能重链的基因来塑造抗体库。
EMBO J. 2025 Sep 5. doi: 10.1038/s44318-025-00552-8.
2
Germline polymorphisms in the immunoglobulin kappa and lambda loci explain variation in the expressed light chain antibody repertoire.免疫球蛋白κ和λ基因座中的种系多态性解释了表达的轻链抗体库的变异。
Res Sq. 2025 Jul 16:rs.3.rs-6994086. doi: 10.21203/rs.3.rs-6994086/v1.
3
Building a neural network model to define DNA sequence specificity in V(D)J recombination.

本文引用的文献

1
Extremely Long-Range Chromatin Loops Link Topological Domains to Facilitate a Diverse Antibody Repertoire.极长距离的染色质环连接拓扑结构域以促进多样化的抗体库形成。
Cell Rep. 2016 Feb 2;14(4):896-906. doi: 10.1016/j.celrep.2015.12.083. Epub 2016 Jan 21.
2
Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes.染色体环结构域指导抗原受体基因的重组。
Cell. 2015 Nov 5;163(4):947-59. doi: 10.1016/j.cell.2015.10.016. Epub 2015 Oct 22.
3
A structural hierarchy mediated by multiple nuclear factors establishes IgH locus conformation.
构建神经网络模型以定义V(D)J重组中的DNA序列特异性。
Nucleic Acids Res. 2025 Jun 20;53(12). doi: 10.1093/nar/gkaf551.
4
Germline polymorphism in the immunoglobulin kappa and lambda loci explain variation in the expressed light chain antibody repertoire.免疫球蛋白κ和λ基因座中的种系多态性解释了表达的轻链抗体库的变异。
bioRxiv. 2025 Jun 1:2025.05.28.656470. doi: 10.1101/2025.05.28.656470.
5
Addressing Technical Pitfalls in Pursuit of Molecular Factors That Mediate Immunoglobulin Gene Regulation.解决技术难题，探索介导免疫球蛋白基因调控的分子因素。
J Immunol. 2024 Sep 1;213(5):651-662. doi: 10.4049/jimmunol.2400131.
6
Molecular basis for differential Igk versus Igh V(D)J joining mechanisms.Igk 与 Igh V(D)J 连接机制差异的分子基础。
Nature. 2024 Jun;630(8015):189-197. doi: 10.1038/s41586-024-07477-y. Epub 2024 May 29.
7
Enhancers within the Ig V Gene Region Orchestrate Chromatin Topology and Regulate V Gene Rearrangement Frequency to Shape the B Cell Receptor Repertoire Specificities.Ig V 基因区域内的增强子协调染色质拓扑结构，并调节 V 基因重排频率，从而塑造 B 细胞受体 repertoire 的特异性。
J Immunol. 2023 Dec 1;211(11):1613-1622. doi: 10.4049/jimmunol.2300261.
8
Molecular Mechanisms of DNA Sequence Selectivity in V(D)J Recombination.V(D)J 重组中 DNA 序列选择性的分子机制
ACS Omega. 2023 Sep 15;8(38):34206-34214. doi: 10.1021/acsomega.3c05601. eCollection 2023 Sep 26.
9
Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes.染色体内和染色体间接触作图揭示了 Igh 基因座具有广泛的构象异质性，并与 B 细胞谱系基因相互作用。
Cell Rep. 2023 Sep 26;42(9):113074. doi: 10.1016/j.celrep.2023.113074. Epub 2023 Sep 6.
10
An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation.IGH 远端增强子通过确定基因座构象调节抗原受体多样性。
Nat Commun. 2023 Mar 3;14(1):1225. doi: 10.1038/s41467-023-36414-2.
由多种核因子介导的结构层次体系建立了免疫球蛋白重链基因座构象。
Genes Dev. 2015 Aug 15;29(16):1683-95. doi: 10.1101/gad.263871.115.
4
A discrete chromatin loop in the mouse Tcra-Tcrd locus shapes the TCRδ and TCRα repertoires.小鼠Tcra-Tcrd基因座中的一个离散染色质环塑造了TCRδ和TCRα库。
Nat Immunol. 2015 Oct;16(10):1085-93. doi: 10.1038/ni.3232. Epub 2015 Aug 10.
5
RAG Represents a Widespread Threat to the Lymphocyte Genome.RAG对淋巴细胞基因组构成广泛威胁。
Cell. 2015 Aug 13;162(4):751-65. doi: 10.1016/j.cell.2015.07.009. Epub 2015 Jul 30.
6
RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement.RUNX1 依赖性 RAG1 沉积引发人类 TCR-δ 基因座重排。
J Exp Med. 2014 Aug 25;211(9):1821-32. doi: 10.1084/jem.20132585. Epub 2014 Aug 18.
7
Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells.抗体库深度测序揭示成熟 B 细胞中抗原非依赖性选择。
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):E2622-9. doi: 10.1073/pnas.1403278111. Epub 2014 Jun 9.
8
The promise and challenge of high-throughput sequencing of the antibody repertoire.高通量测序抗体库的前景与挑战。
Nat Biotechnol. 2014 Feb;32(2):158-68. doi: 10.1038/nbt.2782. Epub 2014 Jan 19.
9
RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.RAG 介导的重组是 ETV6-RUNX1 急性淋巴细胞白血病中致癌重排的主要驱动因素。
Nat Genet. 2014 Feb;46(2):116-25. doi: 10.1038/ng.2874. Epub 2014 Jan 12.
10
Targeted chromatin profiling reveals novel enhancers in Ig H and Ig L chain Loci.靶向染色质谱分析揭示了 IgH 和 IgL 链基因座中的新型增强子。
J Immunol. 2014 Feb 1;192(3):1064-70. doi: 10.4049/jimmunol.1302800. Epub 2013 Dec 18.