The role of germline promoters and I exons in cytokine-induced gene-specific class switch recombination.
Germline transcription precedes class switch recombination (CSR). The promoter regions and I exons of these germline transcripts include binding sites for activation- and cytokine-induced transcription factors, and the promoter regions/I exons are essential for CSR. Therefore, it is a strong hypothesis that the promoter/I exons regions are responsible for much of cytokine-regulated, gene-specific CSR. We tested this hypothesis by swapping the germline promoter and I exons for the murine γ1 and γ2a H chain genes in a transgene of the entire H chain C-region locus. We found that the promoter/I exon for γ1 germline transcripts can direct robust IL-4-induced recombination to the γ2a gene. In contrast, the promoter/I exon for the γ2a germline transcripts works poorly in the context of the γ1 H chain gene, resulting in expression of γ1 H chains that is <1% the wild-type level. Nevertheless, the small amount of recombination to the chimeric γ1 gene is induced by IFN-γ. These results suggest that cytokine regulation of CSR, but not the magnitude of CSR, is regulated by the promoter/I exons.
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. wesadunn@umich.edu
Wesley A
WA
Dunnick
Jian
J
Shi
Victoria
V
Holden
Clinton
C
Fontaine
John T
JT
Collins
D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D016207:Cytokines / Q000502:physiology*; D005091:Exons / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007134:Immunoglobulin Switch Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007438:Introns / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011995:Recombination, Genetic / Q000235:genetics*; D019076:Transgenes
D016207:Cytokines; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region