Regulation of 3' IgH enhancers by a common set of factors, including kappa B-binding proteins.
Targeted disruption of the p50 subunit of NF-kappa B resulted in isotype class switch defects resembling those observed in mice in which the downstream IgH enhancer 3'alpha E(hs1,2) was deleted. We postulated that kappa B binding proteins may regulate class switching by interacting with 3'alpha E(hs1,2) or with other IgH 3' enhancers with which 3'alpha E(hs1,2) synergizes. kappa B binding sites were identified in 3'alpha E(hs1,2) and 3' alpha-hs4, the distal 3' IgH enhancer. A kappa B binding site within 3'alpha E(hs1,2) contributes to at least half the activity of the enhancer in plasma cells, while the same kappa B binding site participates in the complex repression of the enhancer in B cells. In the case of 3'alpha-hs4, a kappa B binding complex activates the enhancer in pre-B, B cells and plasma cells. Additional binding sites within 3'alpha-hs4 for factors known to regulate 3'alpha E(hs1,2), including Oct-1 and BSAP, were identified, and their contribution to 3'alpha-hs4 regulation during B cell development was assessed. Oct-1 positively regulates the enhancer in pre-B and B cells, while BSAP is a repressor in pre-B cells and an activator at the B cell stage. These studies identify kappa B binding proteins as key modulators of 3'alpha E(hs1,2) and 3'alpha-hs4, and suggest coregulation of the two enhancers by a common set of factors.
Michaelson
J S
JS
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Singh
M
M
Snapper
C M
CM
Sha
W C
WC
Baltimore
D
D
Birshtein
B K
BK
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D001666:Binding Sites, Antibody / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004742:Enhancer Elements, Genetic / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005803:Genes, Immunoglobulin / Q000187:drug effects* / Q000276:immunology; D018398:Homeodomain Proteins / Q000378:metabolism; D051863:Host Cell Factor C1; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D050811:Octamer Transcription Factor-1; D051757:PAX5 Transcription Factor; D010950:Plasma Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C497693:Hcfc1 protein, mouse; D018398:Homeodomain Proteins; D051863:Host Cell Factor C1; D007143:Immunoglobulin Heavy Chains; D016328:NF-kappa B; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; C494166:Pou2f1 protein, mouse; D014157:Transcription Factors