A New Hypersensitive Site, HS10, and the Enhancers, E3 ' and Ed, Differentially Regulate Ig kappa Gene Expression

作者：Zhou, Xiaorong; Xiang, Yougui; Ding, Xiaoling; Garrard, William T.^*

来源：The Journal of Immunology, 2012, 188(6): 2722-2732.

DOI：10.4049/jimmunol.1102758

• B-CELL ACTIVATION
• IMMUNOGLOBULIN-KAPPA
• LIGHT-CHAIN
• SOMATIC HYPERMUTATION
• DEVELOPMENTAL-STAGE
• V(D)J RECOMBINATION
• TRANSCRIPTION
• DOWNSTREAM
• CHROMATIN
• SEQUENCE

The mouse Ig kappa gene locus has three known transcriptional enhancers: an intronic enhancer (Ei), a 3' enhancer (E3'), and a further downstream enhancer (Ed). We previously discovered, using the chromosome conformation-capture technique, that Ei and E3' interact with a novel DNA sequence near the 3' end of the Ig kappa locus, specifically in B cells. In the present investigation, we examined the function of this far downstream element. The sequence is evolutionarily conserved and exhibits a plasmacytoma cellspecific DNase I-hypersensitive site in chromatin, henceforth termed HS10 in the locus. HS10 acts as a coactivator of E3' in transient transfection assays. Although HS10(-/-) mice exhibited normal patterns of B cell development, they were tested further along with E3'(-/-) and Ed(-/-) mice for their Ig kappa expression levels in plasma cells, as well as for both allelic and isotype exclusion in splenic B cells. HS10(-/-) and Ed(-/-), but not E3'(-/-), mice exhibited 2.5-fold lower levels of Ig kappa expression in antigenically challenged plasma cells. E3'(-/-) mice, but not HS10(-/-) mice, exhibited impaired IgL isotype and allelic exclusion in splenic B cells. We have suggestive results that Ed may also weakly participate in these processes. In addition, HS10(-/-) mice no longer exhibited regional chromosome interactions with E3', and they exhibited modestly reduced somatic hypermutation in the J kappa-C kappa intronic region in germinal center B cells from Peyer's patches. We conclude that the HS10, E3', and Ed differentially regulate Ig kappa gene dynamics. The Journal of Immunology, 2012, 188: 2722-2732.

• 出版日期2012-3-15
• 单位南通大学