Regulation of Germline Promoters by the Two Human Ig Heavy Chain 3′ α Enhancers

Hu, Yanzhong; Pan, Qiang; Pardali, Evangelia; Mills, Frederick C.; Bernstein, Ralph M.; Max, Edward E.; Sideras, Paschalis; Hammarström, Lennart

doi:10.4049/jimmunol.164.12.6380

Cited by 28 publications

(24 citation statements)

References 51 publications

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“…Although other studies had shown that human 3Ј enhancers were inactive or poorly active (Ͻ4-fold), in human mature B cell lines (18,25) these differences can be attributed to differences in promoter usage and/or efficiencies of transfection. The contribution of NF-B and octamer binding sites to human hs4 enhancer activity a Data are shown as fold activity with respect to the enhancerless constructs.…”

Section: Synergistic Binding To Nf-b and Octamer Sites Controls The Amentioning

confidence: 99%

“…Because targeted deletion of hs3A, which is virtually identical with that of hs3B (16), showed no effect on isotype expression (14), hs4 is likely to play a unique role in this phenotype. In support for a role of 3Ј enhancers in germline transcription, transient transfection assays have shown that both mouse (17) and human (18,19) 3Ј enhancers augmented I region-driven reporter constructs. A role for hs3 and/or hs4 in somatic hypermutation has also been suggested (20); however, the targeted deletion of hs3B and hs4 revealed no effect on somatic hypermutation (21).…”

Section: T He Expression Of Ig H Chain (Igh)mentioning

confidence: 99%

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NF-κB and Oct-2 Synergize to Activate the Human 3′ Igh hs4 Enhancer in B Cells

Sepúlveda

Emelyanov

Birshtein

2004

The Journal of Immunology

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In B cells, the Igh gene locus contains several DNase I-hypersensitive (hs) sites with enhancer activity. These include the 3′ Igh enhancers, which are located downstream of the Cα gene(s) in both mouse and human. In vivo experiments have implicated murine 3′ enhancers, hs3B and/or hs4, in class switching and somatic hypermutation. We previously reported that murine hs4 was regulated by NF-κB, octamer binding proteins, and Pax5 (B cell-specific activator protein). In this study we report that human hs4 is regulated differently. EMSAs and Western analysis of normal B cells before and after stimulation with anti-IgM plus anti-CD40 showed the same complex binding pattern formed by NF-κB, Oct-1, and Oct-2 (but not by Pax5). A similar EMSA pattern was detected in mature human B cell lines (BL-2, Ramos, and HS-Sultan) and in diffuse large B cell lymphoma cell lines, although yin yang 1 protein (YY1) binding was also observed. We have confirmed the in vivo association of these transcription factors with hs4 in B cells by chromatin immunoprecipitation assays. The diffuse large B cell lymphoma cell lines had a distinctive slow-migrating complex containing YY1 associated with Rel-B. We have confirmed by endogenous coimmunoprecipitation an association of YY1 with Rel-B, but not with other NF-κΒ family members. Transient transfection assays showed robust hs4 enhancer activity in the mature B cell lines, which was dependent on synergistic interactions between NF-κB and octamer binding proteins. In addition, human hs4 enhancer activity required Oct-2 and correlated with expression of Oct coactivator from B cells (OCA-B).

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Section: Synergistic Binding To Nf-b and Octamer Sites Controls The Amentioning

confidence: 99%

Section: T He Expression Of Ig H Chain (Igh)mentioning

confidence: 99%

NF-κB and Oct-2 Synergize to Activate the Human 3′ Igh hs4 Enhancer in B Cells

Sepúlveda

Emelyanov

Birshtein

2004

The Journal of Immunology

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“…The role of the complex regulative region in Ig transcription and in the path of maturation of B lymphocytes is not definitively known (Hu et al, 2000;Saleque et al, 1999). Several transcription factors have been shown to be necessary for B cell maturation (Conley, 2003).…”

Section: Introductionmentioning

confidence: 99%

Evolution of human IgH3′EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites

Giambra

Fruscalzo

Giufrè

et al. 2005

Gene

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The enhancer complex regulatory region at the 3V of the immunoglobulin heavy cluster (IgH3VEC) is duplicated in apes along with four constant genes and the region is highly conserved throughout humans. Both human IgH3VECs consist of three loci high sensitive (HS) to DNAse I with enhancer activity. It is thus possible that the presence of structural divergences between the two IgH3VECs and of relative polymorphisms correspond to functional regulatory changes. To analyse the polymorphisms of these almost identical regions, it resulted mandatory to identify the presence of divergent sequences, in order to select distinctive primers for specific PCR genomic amplifications. To this aim, we first compared the two entire IgH3VECs in silicio, utilising the updated GenBank (GB) contigs, then we analysed the two IgH3'ECs by cloning and sequencing amplicons from independent genomes. In silicio analysis showed that several inversions, deletions and short insertions had occurred after the duplication. We analysed in detail, by sequencing specific regions, the polymorphisms occurring in enhancer HS1,2-A (which lies in IgH3VEC-1, 3V to the Ca-1 gene) and in enhancer HS1,2-B (which lies in IgH3VEC-2, 3V to Ca-2). Polymorphisms are due to the repetition (occurring one to four times) of a 38-bp sequence present at the 3V of the core of enhancers HS1,2. The structure of both human HS1,2 enhancers has revealed not yet described polymorphic features due to the presence of variable spacer elements separating the 38-bp repetitions and to variable external elements bordering the repetition cluster. We found that one of the external elements gave rise to a divergent allele 3 in the two clusters. The frequency of the different alleles of the two loci varies in the Italian population and allele 3 of both loci are very rare. The analysis of the Callicebus moloch, Gorilla gorilla and Pan troglodytes HS1,2 enhancers showed the transformation from the ancestral structure with the 31-to the 17-bp external element in hominids.The relevance of the polymorphisms in the HS1,2 enhancers is due to the variable number of binding sites for the transcription factors: NF-nB, CMYB, BSAP1/2, AP1/4, E47, MyoD and AE5 and thus to the possible influence of these variations on switch, production of Ig and on maturation of B cells.

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“…Both regions are involved in class switch and consequently in B lymphocytes maturation (9). These duplicated LCRs at the 3' of both C alpha-1 and C alpha-2 genes, shown in Fig.…”

mentioning

confidence: 99%

Increased frequency of the immunoglobulin enhancer HS1,2 allele 2 in coeliac disease

Frezza

Giambra

Cianci

et al. 2004

Scandinavian Journal of Gastroenterology

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Background: Coeliac disease ( CD) is characterized by increased immunological responsiveness to ingested gliadin in genetically predisposed individuals. This genetic predisposition is not completely defined. A dysregulation of immunoglobulins (Ig) is present in CD: since antiendomysium antibodies (anti-EMA) are of the IgA class. One polymorphic enhancer within the locus control region (LCR) of the immunoglobulin heavy chain cluster at the 3' of the C alpha-1 gene was investigated. The correlation of the penetrance of the four different alleles of the HS1,2-A enhancer of the LCR-1 3' to C alpha-1 in CD patients compared to a control population was analysed. Methods: A total of 115 consecutive CD outpatients, on a gluten-free diet, and 248 healthy donors, age- and sex-matched, from the same geographical area were enrolled in the study. HS1,2-A allele frequencies were investigated by nested polymerase chain reaction (PCR). Results: The frequency of allele 2 of the enhancer HS1,2-A gene was increased by 30.8% as compared to the control frequency. The frequency of homozygosity for allele 2 was significantly increased in CD patients. Crude odds ratio ( OR) showed that those with 2/2 and 2/4 ( OR 2.63, P < 0.001 and OR 2.01, P = 0.03) have a significantly higher risk of developing the disease. In contrast, allele 1/2 may represent a protective genetic factor against CD ( OR 0.52, P = 0.01). Conclusions: These data provide further evidence of a genetic predisposition in CD. Because of the Ig dysregulation in CD, the enhancer HS1,2-A may be involved in the pathogenesis

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Regulation of Germline Promoters by the Two Human Ig Heavy Chain 3′ α Enhancers

Cited by 28 publications

References 51 publications

NF-κB and Oct-2 Synergize to Activate the Human 3′ Igh hs4 Enhancer in B Cells

NF-κB and Oct-2 Synergize to Activate the Human 3′ Igh hs4 Enhancer in B Cells

Evolution of human IgH3′EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites

Increased frequency of the immunoglobulin enhancer HS1,2 allele 2 in coeliac disease

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