Match!

CTCF-binding elements mediate control of V(D)J recombination

Published on Sep 22, 2011in Nature43.07
· DOI :10.1038/NATURE10495
Chunguang Guo13
Estimated H-index: 13
(Harvard University),
Hye Suk Yoon3
Estimated H-index: 3
(Harvard University)
+ 17 AuthorsFrederick W. Alt156
Estimated H-index: 156
(Harvard University)
Sources
Abstract
Immunoglobulin heavy chain (IgH) variable region exons are assembled from VH, D and JH gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the VH and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of DH-proximal VH gene segments and promoting rearrangement of distal VH segments. IGCR1 maintains ordered and lineage-specific VH(D)JH recombination by suppressing VH joining to D segments not joined to JH segments, and VH to DJH joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal VH-to-DJH recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein. The variable region of the immunoglobulin heavy chain (IgH) is generated by selecting one segment each from the VH, D and JH loci. Many studies have proposed the existence of a control region between the VH and D loci that would regulate VH-to-D recombination, but its identity has been elusive. Frederick Alt and colleagues have now located this regulatory sequence, IGCR1 (intergenic control region 1), and show that it uses CTCF sites to promote looping and interaction with distal enhancer elements. It also suppresses other events that would disrupt the ordered rearrangement of the VH, D and JH loci.
  • References (54)
  • Citations (197)
📖 Papers frequently viewed together
201121.52Immunity
10 Authors (Anja Ebert, ..., Meinrad Busslinger)
129 Citations
201136.22Cell
8 Authors (Changying Guo, ..., Ranjan Sen)
113 Citations
201243.07Nature
9 Authors (Jesse R. Dixon, ..., Bing Ren)
3,378 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References54
Newest
#1Shane McManus (IMP: Research Institute of Molecular Pathology)H-Index: 6
#2Anja Ebert (IMP: Research Institute of Molecular Pathology)H-Index: 12
Last. Meinrad Busslinger (IMP: Research Institute of Molecular Pathology)H-Index: 88
view all 9 authors...
Pax5 is a critical regulator of B-cell commitment. Here, we identified direct Pax5 target genes by streptavidin-mediated ChIP-chip analysis of pro-B cells expressing in vivo biotinylated Pax5. By binding to promoters and enhancers, Pax5 directly regulates the expression of multiple transcription factor, cell surface receptor and signal transducer genes. One of the newly identified enhancers was shown by transgenic analysis to confer Pax5-dependent B-cell-specific activity to the Nedd9 gene contr...
94 CitationsSource
#1Stephanie C. Degner (Scripps Research Institute)H-Index: 3
#2Jiyoti Verma-Gaur (Scripps Research Institute)H-Index: 12
Last. Ann J. Feeney (Scripps Research Institute)H-Index: 34
view all 17 authors...
Compaction and looping of the ~2.5-Mb Igh locus during V(D)J rearrangement is essential to allow all VH genes to be brought in proximity with DH-JH segments to create a diverse antibody repertoire, but the proteins directly responsible for this are unknown. Because CCCTC-binding factor (CTCF) has been demonstrated to be involved in long-range chromosomal interactions, we hypothesized that CTCF may promote the contraction of the Igh locus. ChIP sequencing was performed on pro-B cells, revealing c...
163 CitationsSource
#1Anja Ebert (IMP: Research Institute of Molecular Pathology)H-Index: 12
#2Shane McManus (IMP: Research Institute of Molecular Pathology)H-Index: 6
Last. Meinrad Busslinger (IMP: Research Institute of Molecular Pathology)H-Index: 88
view all 10 authors...
129 CitationsSource
#1Eric Pinaud (CNRS: Centre national de la recherche scientifique)H-Index: 20
#2Marie Marquet (CNRS: Centre national de la recherche scientifique)H-Index: 6
Last. Michel Cogné (CNRS: Centre national de la recherche scientifique)H-Index: 41
view all 7 authors...
Antigen receptor gene loci are among the most complex in mammals. The IgH locus, encoding the immunoglobulin heavy chain (IgH) in B-lineage cells, undergoes major transcription-dependent DNA remodeling events, namely V(D)J recombination, Ig class-switch recombination (CSR), and somatic hypermutation (SHM). Various cis-regulatory elements (encompassing promoters, enhancers, and chromatin insulators) recruit multiple nuclear factors in order to ensure IgH locus regulation by tightly orchestrated p...
93 CitationsSource
#1Eric PinaudH-Index: 20
#2Marie MarquetH-Index: 6
Last. Michel CognéH-Index: 41
view all 7 authors...
67 CitationsSource
#1Melissa J. MacPherson (U of T: University of Toronto)H-Index: 2
#2Paul D. Sadowski (U of T: University of Toronto)H-Index: 33
Background The CTCF insulator protein is a highly conserved zinc finger protein that has been implicated in many aspects of gene regulation and nuclear organization. The protein has been hypothesized to organize the human genome by forming DNA loops.
27 CitationsSource
#1Cosmas Giallourakis (HHMI: Howard Hughes Medical Institute)H-Index: 24
#2Andrew FranklinH-Index: 11
Last. Frederick W. AltH-Index: 156
view all 12 authors...
Ig and T-cell receptor (TCR) variable-region gene exons are assembled from component variable (V), diversity (D) and joining (J) gene segments during early B and T cell development. The RAG1/2 endonuclease initiates V(D)J recombination by introducing DNA double-strand breaks at borders of the germ-line segments. In mice, the Ig heavy-chain (IgH) locus contains, from 5′ to 3′, several hundred VH gene segments, 13 D segments, and 4 JH segments within a several megabase region. In developing B cell...
48 CitationsSource
#1Ann J. Feeney (Scripps Research Institute)H-Index: 34
It has been known for over 25 years from the ground-breaking work of Alt and co-workers that the process of V(D)J recombination is under tight regulation, with each of the V(D)J rearrangement steps creating the heterodimeric antigen receptors occurring in a precise order. In addition, although the same RAG recombinase rearranges TCR and Ig genes, there is strict lineage specificity, other than some IgDH to IgJH rearrangement in thymocytes. After making these observations of lineage- and developm...
3 CitationsSource
#1Ramesh Subrahmanyam (NIH: National Institutes of Health)H-Index: 12
#2Ranjan Sen (NIH: National Institutes of Health)H-Index: 27
Abstract The immunoglobulin heavy chain (IgH) gene locus is activated at a precise stage of B lymphocyte development to undergo gene rearrangements that assemble the functional gene. In this review we summarize our current understanding of the chromatin state of the IgH as it appears just prior to the initiation of V(D)J recombination, and the implications of this structure for regulation of recombination. We also examine the role of the intron enhancer, Eμ, in establishing the pre-rearrangement...
12 CitationsSource
#1Stephanie C. Degner-Leisso (Scripps Research Institute)H-Index: 1
#2Ann J. Feeney (Scripps Research Institute)H-Index: 34
Abstract V(D)J recombination is a crucial component of the adaptive immune response, allowing for the production of a diverse antigen receptor repertoire (Ig and TCR). This review will focus on how epigenetic regulation and 3-dimensional (3D) interactions may control V(D)J recombination at Ig loci. The interplay between transcription factors and post-translational modifications at the Igh , Igκ , and Igλ loci will be highlighted. Furthermore, we propose that the spatial organization and epigenet...
34 CitationsSource
Cited By197
Newest
#1Hai-Qiang Dai (HHMI: Howard Hughes Medical Institute)H-Index: 2
#2Hongli Hu (HHMI: Howard Hughes Medical Institute)
Last. Huan Chen (HHMI: Howard Hughes Medical Institute)H-Index: 1
view all 17 authors...
Immunoglobulin heavy chain locus (Igh) VH, D, and JH gene segments are developmentally assembled into V(D)J exons. RAG endonuclease initiates V(D)J recombination by binding a JH-recombination signal sequence (RSS) within a chromatin-based recombination center (RC) and then, in an orientation-dependent process, scans upstream D-containing chromatin presented by cohesin-mediated loop extrusion for convergent D-RSSs to initiate DJH-RC formation1,2. In primary pro-B cells, 100s of upstream VH-associ...
Source
#1Brittney M. Allyn (UPenn: University of Pennsylvania)
#2Kyutae D. Lee (Children's Hospital of Philadelphia)H-Index: 1
Last. Craig H. Bassing (UPenn: University of Pennsylvania)H-Index: 45
view all 3 authors...
The past decade has increased our understanding of how genome topology controls RAG endonuclease-mediated assembly of lymphocyte AgR genes. New technologies have illuminated how the large IgH, Igkappa, TCRalpha/delta, and TCRbeta loci fold into compact structures that place their numerous V gene segments in similar three-dimensional proximity to their distal recombination center composed of RAG-bound (D)J gene segments. Many studies have shown that CTCF and cohesin protein-mediated chromosome lo...
Source
#1Jeannine A Ott (A&M: Texas A&M University)H-Index: 2
#2Jenna Harrison (A&M: Texas A&M University)
Last. Michael F. Criscitiello (A&M: Texas A&M University)H-Index: 22
view all 4 authors...
In addition to canonical T and B cell receptors, cartilaginous fish assemble non-canonical T cell receptors (TCR) that employ various B cell components. For example, shark T cells associate alpha (TCR-alpha) or delta (TCR-delta) constant (C) regions with immunoglobulin (Ig) heavy chain (H) variable (V) segments or TCR-associated Ig-like V (TAILV) segments to form chimeric IgV-T cell receptors, and combine TCRdeltaC with both Ig-like and TCR-like V segments to form the doubly-rearranging NAR-TCR....
Source
#1Iman Dalloul (University of Limoges)H-Index: 2
#2Zeinab Dalloul (University of Limoges)H-Index: 3
Last. Michel Cogné (University of Limoges)H-Index: 41
view all 7 authors...
Source
#1Ao Sun (CAS: Chinese Academy of Sciences)
#2Ke Xu (CAS: Chinese Academy of Sciences)H-Index: 14
Last. Yanhong Ji (Xi'an Jiaotong University)
view all 13 authors...
The recombination activating gene (RAG or RAG1/RAG2 complex)-mediated adaptive immune system is a hallmark of jawed vertebrates. It has been reported that RAG originated in invertebrates. However, whether RAG further evolved once it arose in jawed vertebrates remains largely unknown. Here, we found that zebrafish RAG (zRAG) had a lower activity than mouse RAG (mRAG). Intriguingly, the attenuated stability of zebrafish RAG2 (zRAG2), but not zebrafish RAG1, caused the reduced V(D)J recombination e...
Source
#1Gerson Rothschild (Columbia University)H-Index: 9
#2Wanwei Zhang (Columbia University)H-Index: 1
Last. Zhi-Ping Liu (SDU: Shandong University)H-Index: 26
view all 14 authors...
B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell–specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs,...
1 CitationsSource
#1Coline Arnould (University of Toulouse)H-Index: 3
#2Gaëlle Legube (University of Toulouse)H-Index: 28
Abstract DNA double-strand breaks (DSBs) are harmful lesions that severely challenge genomic integrity, and recent evidence suggests that DSBs occur more frequently on the genome than previously thought. These lesions activate a complex and multilayered response called the DNA damage response, which allows to coordinate their repair with the cell cycle progression. While the mechanistic details of repair processes have been narrowed, thanks to several decades of intense studies, our knowledge of...
4 CitationsSource
Last. Said AoufouchiH-Index: 3
view all 4 authors...
Source
We describe a Kappa-on-Heavy (KoH) mouse that produces a class of highly diverse, fully human, antibody-like agents. This mouse was made by replacing the germline variable sequences of both the Ig heavy-chain (IgH) and Ig kappa (IgK) loci with the human IgK germline variable sequences, producing antibody-like molecules with an antigen binding site made up of 2 kappa variable domains. These molecules, named KoH bodies, structurally mimic naturally existing Bence-Jones light-chain dimers in their ...
Source
#1Zhaoqing Ba (HHMI: Howard Hughes Medical Institute)H-Index: 3
#1Zhaoqing Ba (HHMI: Howard Hughes Medical Institute)H-Index: 6
Last. Frederick W. Alt (HHMI: Howard Hughes Medical Institute)H-Index: 156
view all 9 authors...
RAG endonuclease initiates V(D)J recombination in progenitor (pro)-B cells1. Upon binding a recombination center (RC)-based JH, RAG scans upstream chromatin via loop extrusion, potentially mediated by cohesin2-10, to locate Ds and assemble a DJH-based RC11. CTCF looping factor-bound elements (CBEs) within IGCR1 upstream of Ds impede RAG-scanning12-15; but their inactivation allows scanning to proximal VHs where additional CBEs activate rearrangement and impede scanning any further upstream15,16....
1 CitationsSource