The IgH locus 3′ cis-regulatory super-enhancer co-opts AID for allelic transvection

Noir, Sandrine Le; Laffleur, Brice; Carrion, Claire; Garot, Armand; Lecardeur, Sandrine; Pinaud, Eric; Denizot, Yves; Skok, Jane A.; Cogné, Michel

doi:10.18632/oncotarget.14585

Cited by 18 publications

(15 citation statements)

References 39 publications

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“…This fits with a model where the 3’RR would participate in the assembly of a CSR factory, bringing both the loops formed in cis on a targeted locus, and potential other legitimate targets from other chromosomes (usually the other IgH allele but also here a knocked-in Igκ KIKS allele). This schema must thus accommodate not only the “loop model” [ 19 ] but also the data concurring to demonstrate the efficient interactions of S regions even when located on different chromosomes [ 27 , 28 , 35 , 36 ].…”

Section: Resultsmentioning

confidence: 99%

IgH 3’ regulatory region increases ectopic class switch recombination

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

IgH 3’ regulatory region increases ectopic class switch recombination

et al. 2021

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“…The 3’RR is a strong super-enhancer regulating remodeling of the IgH locus in mature B cells and was even recently shown to have trans -acting effects on the other IgH allele ( 1 , 25 ). Full deletion of the 3’RR was previously reported to strongly impact CSR, SHM and the IgH boosted expression which ensures high antibody secretion by plasma cells ( 6 , 10 ).…”

Section: Discussionmentioning

confidence: 99%

Functional anatomy of the immunoglobulin heavy chain 3΄ super-enhancer needs not only core enhancer elements but also their unique DNA context

Noir

Boyer

Lecardeur

et al. 2017

Nucleic Acids Research

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Cis-regulatory elements feature clustered sites for transcription factors, defining core enhancers and have inter-species homology. The mouse IgH 3΄ regulatory region (3’RR), a major B-cell super-enhancer, consists of four of such core enhancers, scattered throughout more than 25 kb of packaging ‘junk DNA’, the sequence of which is not conserved but follows a unique palindromic architecture which is conserved in all mammalian species. The 3’RR promotes long-range interactions and potential IgH loops with upstream promoters, controlling class switch recombination (CSR) and somatic hypermutation (SHM). It was thus of interest to determine whether this functional architecture also involves the specific functional structure of the super-enhancer itself, potentially promoted by its symmetric DNA shell. Since many transgenic 3’RR models simply linked core enhancers without this shell, it was also important to compare such a ‘core 3’RR’ (c3’RR) with the intact full-length super-enhancer in an actual endogenous IgH context. Packaging DNA between 3’RR core enhancers proved in fact to be necessary for optimal SHM, CSR and IgH locus expression in plasma cells. This reveals that packaging DNA can matter in the functional anatomy of a super-enhancer, and that precise evaluation of such elements requires full consideration of their global architecture.

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“…Sequences were analyzed using FinchTV software and aligned with MultAlin (http://multalin.toulouse.inra.fr/multalin/) and the λ VJ rearrangement was determinated using IMGT/V-QUEST tool (http://imgt.org/). [15][16][17] High-Throughput sequencing on ROCHE 454 sequencer Transcripts were amplified using 5' RACE-PCR and consensus reverse primers hybridizing in λ constant exons as previously described 18,19 and sequenced on a 454 sequencer (Roche).…”

Section: Topo Cloning and Sequencingmentioning

confidence: 99%

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Bender

Javaugue

Saintamand

et al. 2019

Preprint

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POEMS syndrome is a rare multisystem disease due to an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected, due to the highly restrictive usage of two λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations following PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (RACE-RepSeq), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 85% of patients with POEMS syndrome, including some in whom bone marrow tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ + monoclonal PCs. Twenty-four of the 30 LC clonal sequences found (80%) were derived from the IGLV1-40 and IGLV1-44 germline genes, two from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid and specific tool to detect low-abundance PC clones in BM, and assign them to POEMS syndrome, with all the consequences for therapeutic options hereby.

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The IgH locus 3′ cis-regulatory super-enhancer co-opts AID for allelic transvection

Cited by 18 publications

References 39 publications

IgH 3’ regulatory region increases ectopic class switch recombination

IgH 3’ regulatory region increases ectopic class switch recombination

Functional anatomy of the immunoglobulin heavy chain 3΄ super-enhancer needs not only core enhancer elements but also their unique DNA context

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

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