Mechanism and regulation of class switch recombination by IgH transcriptional control elements

Oudinet, Chloé; Braikia, Fatima-Zohra; Dauba, Audrey; Khamlichi, Ahmed Amine

doi:10.1016/bs.ai.2020.06.003

Cited by 16 publications

(42 citation statements)

References 191 publications

(368 reference statements)

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“…The only exception is IgG1, whose switch region is minimally regulated by the 3′ IgHRR enhancers. In retrospect, the failures of observing a CSR defect in previous studies are due to incomplete deletions of the CBEs (3) or usage of a cell line (2) where the 3′IgHRR is preactivated (7). Thus, this study unequivocally establishes an important role of the 3′IgH CBEs in physiological CSR.…”

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confidence: 54%

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An insulator that regulates chromatin extrusion and class switch recombination

2021

Proc. Natl. Acad. Sci. U.S.A.

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confidence: 54%

“…CSR is initiated by the B cell-specific enzyme activation-induced cytidine deaminase (AID), and is under complex regulation involving multiple transcription enhancers, promoters, and CBEs. [Readers are encouraged to see an excellent review by Oudinet et al (7) and the references therein. ]…”

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confidence: 99%

An insulator that regulates chromatin extrusion and class switch recombination

2021

Proc. Natl. Acad. Sci. U.S.A.

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“…187 Mechanistically, type I IFNs and IFN-γ could promote antibody isotype switching into IgG. 189 , 190 The regulation of class switch recombination is largely dependent on germline (GL) transcription, which means that distinct cytokines determine the isotypes of antibodies synthesized by B cells by inducing different transcription factors targeting various cytokine-responsive elements accompanied by GL promoters. 191 STAT1 and T-bet, induced by IFN signaling, 192 , 193 are both important transcriptional activators for IgG germline transcription.…”

Section: Ifns Regulate the Cancer-immunity Cyclementioning

confidence: 99%

Double-edged effects of interferons on the regulation of cancer-immunity cycle

et al. 2021

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Interferons (IFNs) are a large family of pleiotropic cytokines that regulate both innate and adaptive immunity and show anti-cancer effects in various cancer types. Moreover, it was revealed that IFN signaling plays critical roles in the success of cancer therapy strategies, thereby enhancing their therapeutic effects. However, IFNs have minimal or even adverse effects on cancer eradication, and mediate cancer immune escape in some instances. Thus, IFNs have a double-edged effect on the cancer immune response. Recent studies suggest that IFNs regulate each step of the cancer immunity-cycle, consisting of cancer antigen release, presentation of antigens and activation of T cells, trafficking and infiltration of effector T cells into the tumor microenvironment, and recognition and killing of cancer cells, which contributes to our understanding of the mechanisms of IFNs in regulating cancer immunity. In this review, we focus on IFNs and cancer immunity and elaborate on the roles of IFNs in regulating the cancerimmunity cycle.

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“…Mature B cells undergo immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) to change the constant region of IgH chains and modulate antibody effector functions (1, 2). Transcription from IgH V(D)J exons runs through proximal Cμ exons that specify IgM antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…Transcription from IgH V(D)J exons runs through proximal Cμ exons that specify IgM antibodies. Upon activation, B cells undergo CSR to replace Cμ with one of six sets of constant region exons (C H s ) to produce other antibody isotypes (IgG, IgE or IgA) (2, 3). The intronic enhancer (iEμ), located at the 5’ end, and 3’IgH regulatory region (3’IgHRR) super-enhancer, located at the 3’ end, of the IgH constant region locus both contribute to CSR (4–9).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Yoon

Williams

et al. 2020

Preprint

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IgH 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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Mechanism and regulation of class switch recombination by IgH transcriptional control elements

Cited by 16 publications

References 191 publications

An insulator that regulates chromatin extrusion and class switch recombination

An insulator that regulates chromatin extrusion and class switch recombination

Double-edged effects of interferons on the regulation of cancer-immunity cycle

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

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