Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3â€² Regulatory Region

Birshtein, Barbara K.

doi:10.3389/fimmu.2014.00163

Cited by 36 publications

(42 citation statements)

References 80 publications

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“…There is no doubt that the 3′RR plays a key role in IgH locus regulation (39) but the role of the conserved quasi-palindrome and the hierarchy between the modules remained poorly understood. By comparing relevant KO mouse models, our study demonstrated that the 3′RR includes at least two functional modules: (i) the distal module, which includes the hs4 enhancer element; and (ii) the proximal module, defined as the 3′RR quasipalindrome.…”

Section: Discussionmentioning

confidence: 99%

“…In B-lineage precursors, a first contribution was assigned to CBEs, which have been proposed to facilitate interactions between locus distant regions (14,20,41,42). Deletion of hs5-7 CBEs downstream from the mouse 3′RR resulted in only a slight modification of D and V H use (16), suggesting a modest contribution of 3′ CBEs in VDJ joining, although it is not excluded that full deletion (including hs8) might have a more drastic effect (39). Once VDJ recombination is completed, the 3′RR and the promoter of the VDJ-rearranged segment continue to interact and then starts the actual 3′RR stepwise transcriptional activation by its distal module.…”

Section: Discussionmentioning

confidence: 99%

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Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Garot

Marquet

Saintamand

et al. 2016

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

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As a master regulator of functional Ig heavy chain (IgH) expression, the IgH 3′ regulatory region (3′RR) controls multiple transcription events at various stages of B-cell ontogeny, from newly formed B cells until the ultimate plasma cell stage. The IgH 3′RR plays a pivotal role in early B-cell receptor expression, germ-line transcription preceding class switch recombination, interactions between targeted switch (S) regions, variable region transcription before somatic hypermutation, and antibody heavy chain production, but the functional ranking of its different elements is still inaccurate, especially that of its evolutionarily conserved quasipalindromic structure. By comparing relevant previous knockout (KO) mouse models (3′RR KO and hs3b-4 KO) to a novel mutant devoid of the 3′RR quasi-palindromic region (3′PAL KO), we pinpointed common features and differences that specify two distinct regulatory entities acting sequentially during B-cell ontogeny. Independently of exogenous antigens, the 3′RR distal part, including hs4, fine-tuned B-cell receptor expression in newly formed and naïve B-cell subsets. At mature stages, the 3′RR portion including the quasi-palindrome dictated antigen-dependent locus remodeling (global somatic hypermutation and class switch recombination to major isotypes) in activated B cells and antibody production in plasma cells.immunoglobulin gene regulation | enhancers | B-cell development I mmunoglobulin heavy chain (IgH) expression is critical for B-cell development and survival. In developing B-lineage cells, accessibility to the major remodeling events [VDJ recombination, somatic hypermutation (SHM), class switch recombination (CSR), and locus suicide recombination] depends on epigenetic changes and germ-line transcription of many regions, including V H promoters, I/switch region promoters, cis-regulatory region enhancers, and chromatin insulators (1-3). A focus on knockout (KO) models for IgH cis-regulatory regions (enhancers and chromatin insulators) is a means to simplify the regulation picture. At the preproB stage, the IgH locus undergoes long-range looping in a "rosette-like" structure that brings into close proximity major IgH regulatory regions, such as the V H to D H intergenic control regions (IGCR1 and -2), the Eμ intronic enhancer, the 3′ regulatory region (3′RR), and the 3′IgH CTCF-binding elements (CBEs) (4-6). Initiation of VDJ recombination is assisted by the Eμ enhancer, which provides efficient transcription and accessibility to initiate D H to J H rearrangements (7-10), as well as the IGCR1 and -2 elements that ordinate the V H to DJ H second recombination step (5, 11-13). Devoid of enhancer activity (14, 15), 3′CBE (hs5 to hs8) likely participate in IgH folding before VDJ recombination because deletion of hs5 to -7 only impacts use of proximal V H regions (16). In pre-B cells, once a functional H chain is expressed as a component of the pre-B-cell recptor (BCR), the Eμ enhancer function switches from DJ H region accessibility to Igμ chain expression, and consequent...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Garot

Marquet

Saintamand

et al. 2016

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

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“…How the 3=RR can mediate its silencing activity is presently unknown and may involve a developmental stage-dependent interplay between the topological reorganization of the IgH locus, which may be modulated by CTCF insulators and transcription factor-mediated loops, posttranslational modifications of factors such as CTCF, and the 3=RR epigenetic modifications and recruitment of transcription factors and corepressors (48)(49)(50)(51). Interestingly, there is some evidence that the human ␤-globin locus control region can in some contexts repress gene expression through transcriptional interference, potentially involving transcripts initiating in flanking repetitive sequences and running through the ␤-globin locus (52).…”

Section: Discussionmentioning

confidence: 99%

Developmental Switch in the Transcriptional Activity of a Long-Range Regulatory Element

Braikia

Conte

Moutahir

et al. 2015

Molecular and Cellular Biology

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e Eukaryotic gene expression is often controlled by distant regulatory elements. In developing B lymphocytes, transcription is associated with V(D)J recombination at immunoglobulin loci. This process is regulated by remote cis-acting elements. At the immunoglobulin heavy chain (IgH) locus, the 3= regulatory region (3=RR) promotes transcription in mature B cells. This led to the notion that the 3=RR orchestrates the IgH locus activity at late stages of B cell maturation only. However, long-range interactions involving the 3=RR were detected in early B cells, but the functional consequences of these interactions were unknown. Here we show that not only does the 3=RR affect transcription at distant sites within the IgH variable region but also it conveys a transcriptional silencing activity on both sense and antisense transcription. The 3=RR-mediated silencing activity is switched off upon completion of V H -DJ H recombination. Our findings reveal a developmentally controlled, stage-dependent shift in the transcriptional activity of a master regulatory element. The spatial and temporal control of gene expression in metazoans is effected by regulatory elements that are often located far from gene promoters (1). This pattern of gene expression regulation is a hallmark of antigen receptor loci, whose expression involves both transcription and recombination. The mouse IgH locus contains ϳ195 variable (V H ) genes subdivided into domainorganized gene families, including the distal V H family, by far the largest, and the proximal V H family. The V H genes are followed by a dozen diversity (D) segments, 4 joining (J H ) segments, and 8 constant (C H ) genes (2, 3) (Fig. 1A, top scheme). The assembly of an IgH variable region exon through V(D)J recombination occurs in early developing B cells in an ordered manner, first D to J H and then V H to DJ H . While the first recombination step (D-J H ) can also be detected in developing T cells, V H -DJ H recombination is strictly B cell specific (4).In addition to its B cell lineage specificity, V H -DJ H rearrangement is regulated by allelic exclusion, which enables monoallelic expression of only one IgH locus by a given B cell (4, 5). In this process, a productive V(D)J rearrangement on one allele ultimately leads to surface expression of a heavy chain which signals arrest of V H -DJ H recombination on the second allele. If the first rearrangement is not productive (i.e., no heavy chain production), then the second allele can undergo V H -DJ H recombination (4, 5). There is considerable evidence to support the notion that V H -DJ H rearrangement is the regulated step in IgH allelic exclusion and its maintenance through a feedback mechanism (4, 5), although the molecular mechanisms through which feedback signaling inhibits V H -DJ H recombination remain unclear.Another level of regulation of V H -DJ H recombination relates to the physical location of V H gene segments within the variable domain. Indeed, several gene-targeted studies showed that recombinations of the distal and p...

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“…Factors such as YY1, PAX5, IKAROS, CTCF, and Cohesin play important roles in various aspects of long-range events at the IgH locus, including V(D)J recombination, CSR, and promoter/enhancer and enhancer/enhancer interactions (3)(4)(5)(6). Multiple CTCF binding elements (CBEs) were reported along the IgH locus.…”

mentioning

confidence: 99%

“…This entails a long-range control of multiple upstream I promoters (6,13). Gene-targeted deletion of individual enhancers had no effect on GL transcription (14-16).…”

mentioning

confidence: 99%

Inducible CTCF insulator delays the IgH 3′ regulatory region-mediated activation of germline promoters and alters class switching

Braikia

Oudinet

Haddad

et al. 2017

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

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Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to switch from IgM expression to the expression of downstream isotypes. CSR is preceded by inducible germline (GL) transcription of the constant genes and is controlled by the 3′ regulatory region (3′RR) in a stimulus-dependent manner. Why the 3′RR-mediated upregulation of GL transcription is delayed to the mature B-cell stage is presently unknown. Here we show that mice devoid of an inducible CTCF binding element, located in the α constant gene, display a marked isotype-specific increase of GL transcription in developing and resting splenic B cells and altered CSR in activated B cells. Moreover, insertion of a GL promoter downstream of the CTCF insulator led to premature activation of the ectopic promoter. This study provides functional evidence that the 3′RR has a developmentally controlled potential to constitutively activate GL promoters but that this activity is delayed, at least in part, by the CTCF insulator, which borders a transcriptionally active domain established by the 3′RR in developing B cells. E xpression of complex loci is developmentally programmed or induced by specific stimuli and is often controlled by distant regulatory elements within relatively large chromatin domains. Transcriptional and architectural factors play an important role in the establishment and maintenance of these domains and facilitate long-range interactions between regulatory elements and target promoters (1, 2). The Ig heavy chain (IgH) locus is expressed in a lineage-and developmental stage-dependent manner. Various cis-acting elements including promoters, enhancers, and insulators control IgH locus expression and are engaged in multiple long-range interactions (3, 4).Factors such as YY1, PAX5, IKAROS, CTCF, and Cohesin play important roles in various aspects of long-range events at the IgH locus, including V(D)J recombination, CSR, and promoter/enhancer and enhancer/enhancer interactions (3-6). Multiple CTCF binding elements (CBEs) were reported along the IgH locus. The majority of these CBEs lie within the variable domain (7), and two CBEs were identified within the V H -D intergenic region (7-9). At the 3′ end of the locus, ∼10 CBEs were identified downstream of the 3′RR and are thought to delineate the 3′ border of the IgH locus (10). More recently, a discrete CBE was identified within the α constant gene (11), but its role in vivo is presently unknown.Upon antigen challenge, mature B cells can undergo CSR that allows B cells to change the heavy-chain constant domain of an IgM to IgG, IgE, or IgA. CSR to a particular isotype is induced by specific external stimuli, including antigens, mitogens, cytokines, and intercellular interactions. CSR is mediated by highly repetitive sequences called switch (S) sequences located upstream of the constant exons and is preceded by germline (GL) transcription of the S sequences that originates from GL promoters, named I promoters (12).The 3′RR is composed of four enhance...

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Epigenetic Regulation of Individual Modules of the immunoglobulin heavy chain locus 3â€² Regulatory Region

Cited by 36 publications

References 80 publications

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Sequential activation and distinct functions for distal and proximal modules within the IgH 3′ regulatory region

Developmental Switch in the Transcriptional Activity of a Long-Range Regulatory Element

Inducible CTCF insulator delays the IgH 3′ regulatory region-mediated activation of germline promoters and alters class switching

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