Allele-specific repression of lymphotoxin-alpha by activated B cell factor-1.
Genetic variation at the human LTA locus, encoding lymphotoxin-alpha, is associated with susceptibility to myocardial infarction, asthma and other diseases. By detailed haplotypic analysis of the locus, we identified a single-nucleotide polymorphism (SNP) at LTA+80 as a main predictor of LTA protein production by human B cells. We found that activated B-cell factor-1 (ABF-1) binds to this site in vitro and suppresses reporter gene expression, but only in the presence of the LTA+80A allele. Using haplotype-specific chromatin immunoprecipitation, we confirmed that ABF-1 is preferentially recruited to the low-producer allele in vivo. These findings provide a molecular model of how LTA expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1.
Knight
Julian C
JC
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. julian@well.ox.ac.uk
Keating
Brendan J
BJ
Kwiatkowski
Dominic P
DP
D000483:Alleles; D002461:Cell Line, Transformed; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics*; D010957:Plasmids; D011233:Precipitin Tests
D008233:Lymphotoxin-alpha