scholarly journals The IgH 3′ regulatory region super-enhancer does not control IgA class switch recombination in the B1 lineage

2017 ◽  
Vol 15 (3) ◽  
pp. 289-291 ◽  
Author(s):  
Hussein Issaoui ◽  
Nour Ghazzaui ◽  
Alexis Saintamand ◽  
Claire Carrion ◽  
Christelle Oblet ◽  
...  
Keyword(s):  
Regulatory Region ◽  
Class Switch Recombination ◽  
Class Switch ◽  
Super Enhancer

scholarly journals Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination

2020 ◽  
Vol 5 (44) ◽  
pp. eaay5864 ◽  
Author(s):  
Gerson Rothschild ◽  
Wanwei Zhang ◽  
Junghyun Lim ◽  
Pankaj Kumar Giri ◽  
Brice Laffleur ◽  
...  
Keyword(s):  
B Cells ◽  
Regulatory Region ◽  
Noncoding Rnas ◽  
Class Switch Recombination ◽  
Regulatory Elements ◽  
Specific Class ◽  
Antibody Diversity ◽  
Variable Regions ◽  
Class Switch ◽  
Super Enhancer

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, and the activity of the 3′ regulatory region (3′RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome–deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer’s patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3′RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer’s patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.

scholarly journals IgH 3’ regulatory region increases ectopic class switch recombination

PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1009288
Author(s):  
Sandrine Le Noir ◽  
Amélie Bonaud ◽  
Bastien Hervé ◽  
Audrey Baylet ◽  
François Boyer ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
Dna Lesions ◽  
Reporter System ◽  
Long Distance ◽  
Class Switch ◽  
Super Enhancer ◽  
Switch Regions ◽  
Activation Induced Deaminase

DNA lesions inflicted by activation-induced deaminase (AID) instrumentally initiate the processes reshaping immunoglobulin genes in mature B-cells, from local somatic hypermutation (SHM) to junctions of distant breaks during class switch recombination (CSR). It remains incompletely understood how these divergent outcomes of AID attacks are differentially and temporally focused, with CSR strictly occurring in the Ig heavy chain (IgH) locus while SHM concentrates on rearranged V(D)J regions in the IgH and Ig light chain loci. In the IgH locus, disruption of either the 3’Regulatory Region (3’RR) super-enhancer or of switch (S) regions preceding constant genes, profoundly affects CSR. Reciprocally, we now examined if these elements are sufficient to induce CSR in a synthetic locus based on the Igκ locus backbone. Addition of a surrogate “core 3’RR” (c3’RR) and of a pair of transcribed and spliced Switch regions, together with a reporter system for “κ-CSR” yielded a switchable Igκ locus. While the c3’RR stimulated SHM at S regions, it also lowered the local SHM threshold necessary for switch recombination to occur. The 3’RR thus both helps recruit AID to initiate DNA lesions, but then also promotes their resolution through long-distance synapses and recombination following double-strand breaks.

scholarly journals IgD class switch recombination is not controlled through the immunoglobulin heavy chain 3′ regulatory region super-enhancer

2017 ◽  
Vol 14 (10) ◽  
pp. 871-874 ◽  
Author(s):  
Hussein Issaoui ◽  
Nour Ghazzaui ◽  
Alexis Saintamand ◽  
Yves Denizot ◽  
François Boyer
Keyword(s):  
Heavy Chain ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
Immunoglobulin Heavy Chain ◽  
Class Switch ◽  
Super Enhancer

Genomic deletion of the whole IgH 3′ regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1895-1898 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Remi Fiancette ◽  
Eric Pinaud ◽  
Véronique Truffinet ◽  
Nadine Cogné ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
B Cell Differentiation ◽  
Plasma Cell Differentiation ◽  
Heavy Chains ◽  
Class Switch ◽  
Transcriptional Changes

Abstract The immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation. In progenitor B cells, V(D)J assembly allows expression of μ heavy chains. In mature B cells, class switch recombination may replace the expressed constant (C)μ gene with a downstream CH gene. Finally, plasma cell differentiation strongly boosts IgH transcription. How the multiple IgH transcriptional enhancers tune these changes is unclear. Here we demonstrate that deletion of the whole IgH 3′ regulatory region (3′RR) allows normal maturation until the stage of IgM/IgD expressing lymphocytes, but nearly abrogates class switch recombination to all CH genes. Although plasma cell numbers are unaffected, we reveal the role of the 3′RR into the transcriptional burst normally associated with plasma cell differentiation. Our study shows that transcriptional changes and recombinations occurring after antigen-encounter appear mainly controlled by the 3′RR working as a single functional unit.

scholarly journals Class-Switch Recombination in the Absence of the IgH 3′ Regulatory Region

2016 ◽  
Vol 197 (7) ◽  
pp. 2930-2935 ◽  
Author(s):  
Ahrom Kim ◽  
Li Han ◽  
Gabriel E. Santiago ◽  
Ramiro E. Verdun ◽  
Kefei Yu
Keyword(s):  
Regulatory Region ◽  
Class Switch Recombination ◽  
Class Switch

scholarly journals Physiological role of the 3’IgH CBEs super-anchor in antibody class switching

2020 ◽  
Author(s):  
Xuefei Zhang ◽  
Hye Suk Yoon ◽  
Aimee M. Chapdelaine-Williams ◽  
Nia Kyritsis ◽  
Frederick W. Alt
Keyword(s):  
Chromosomal Rearrangements ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
Physiological Role ◽  
Ctcf Binding ◽  
Dna Breaks ◽  
Antibody Isotype ◽  
Class Switch ◽  
Igh Locus ◽  
Antibody Class

ABSTRACTIgH class switch recombination (CSR) replaces Cμ constant region (CH) exons with one of six downstream CHS by joining transcription-targeted DSBs in the Cμ switch (S) region to DSBs in a downstream S region. Chromatin loop extrusion underlies fundamental CSR mechanisms including 3’IgH regulatory region (3’IgHRR)-mediated S region transcription, CSR center formation, and deletional CSR joining. There are ten consecutive CTCF binding elements (CBEs) downstream of the 3’IgHRR, termed the “3’IgH CBEs”. Prior studies showed that deletion of eight 3’IgH CBEs did not detectably affect CSR. Here, we report that deletion of all 3’IgH CBEs impacts, to varying degrees, germline transcription and CSR of upstream S regions, except Sγ1. Moreover, deletion of all 3’IgH CBEs rendered the 6kb region just downstream highly transcribed and caused sequences within to be aligned with Sμ, broken, and joined to form aberrant CSR rearrangements. These findings implicate the 3’IgH CBEs as a critical insulator for focusing loop extrusion-mediated 3’IgHRR transcriptional and CSR activities on upstream CH locus targets.SignificanceB lymphocytes change antibody heavy chain (IgH) isotypes by a recombination/deletion process called IgH class switch recombination (CSR). CSR involves introduction of DNA breaks into a donor switch (S) region and also into one of six downstream S regions, with joining of the breaks changing antibody isotype. A chromatin super-anchor, of unknown function, is located just downstream of the IgH locus. We show that complete deletion of this super-anchor variably decreases CSR to most S regions and creates an ectopic S region downstream of IgH locus that undergoes aberrant CSR-driven chromosomal rearrangements. Based on these and other findings, we conclude that the super-anchor downstream of IgH is a critical insulator for focusing potentially dangerous CSR rearrangements to the IgH locus.

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