Position and sequence conservation in Amniota of polymorphic enhancer HS1.2 within the palindrome of IgH 3'Regulatory Region

D’Addabbo, Pietro; Scascitelli, Moira; Giambra, Vincenzo; Rocchi, Mariano; Frezza, Domenico

doi:10.1186/1471-2148-11-71

Cited by 28 publications

(61 citation statements)

References 37 publications

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“…A similar quasi-palindromic organization is conserved in the 3′RR of other species, including humans and apes (3,35,36). Strikingly, evolution did not conserve virtual homology of 3′RR inverted regions but preserved its global structure.…”

Section: Significancementioning

confidence: 70%

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: Significancementioning

confidence: 70%

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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“…The binding of HS1.2 and HS4 enhancers to nuclear protein complexes including NF-κB has previously been demonstrated 29–31. The difference between HS1.2 allele *1 and *2 could affect the three-dimensional structure associated with the region encompassing the specific palindromic structure on both sides of the HS1.2,11 thus affecting spatial localisation of the enhancers in germline transcription and subsequent events of the class switch recombination 38 39. Furthermore, the protein DNA complexes could affect the efficiency of the interaction with different alleles of HS1.2 and reduce or facilitate the looping and positioning of the enhancer near the promoter, as shown by 3C experiments in mice 40 41…”

Section: Discussionmentioning

confidence: 97%

“…Three enhancers are located in each 3′RR where the HS1.2 enhancer is central to a palindromic region conserved also in mice (figure 1). 10 This structure was conserved in mammals for complementarity but not for sequence, suggesting an advantage at the three-dimensional level in the maintenance of the palindrome 11. While HS3 and HS4 enhancers in human 3′RR-1 are identical to those in 3′RR-2, the HS1.2 enhancer is polymorphic, with variable numbers of tandem repeats and spacers accompanied by predicted differences in transcription factor binding sites 12 13.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus

et al. 2012

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“…30 The effect of the 39RR on B1 B-cell m transcription (the most ancestral specific B-cell function) and B1 B-cell fate is coherent with its similar role on B2 B cells. Of interest, deletion of the 39RR was reported to strongly reduce levels of MZ B2 B cells.…”

Section: Discussionmentioning

confidence: 85%

The immunoglobulin heavy chain 3′ regulatory region superenhancer controls mouse B1 B-cell fate and late VDJ repertoire diversity

et al. 2018

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Key Points• Similar to B2 B cells, the IgH 39RR superenhancer controls m-chain transcription and cell fate in B1 B cells.• In contrast to B2 B cells, deletion of the IgH 39RR superenhancer affects B1 B-cell late repertoire diversity. control during B-cell maturation. For the first time, these results highlight the contribution of the 39RR superenhancer at this interface between innate and acquired immunity.

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Position and sequence conservation in Amniota of polymorphic enhancer HS1.2 within the palindrome of IgH 3'Regulatory Region

Cited by 28 publications

References 37 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

Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus

The immunoglobulin heavy chain 3′ regulatory region superenhancer controls mouse B1 B-cell fate and late VDJ repertoire diversity

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