Knight Julian C, Keating Brendan J, Kwiatkowski Dominic P
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Nat Genet. 2004 Apr;36(4):394-9. doi: 10.1038/ng1331. Epub 2004 Mar 28.
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.
人类LTA基因座（编码淋巴毒素α）的遗传变异与心肌梗死、哮喘及其他疾病的易感性相关。通过对该基因座进行详细的单倍型分析，我们确定LTA +80位点的一个单核苷酸多态性（SNP）是人类B细胞产生LTA蛋白的主要预测指标。我们发现，活化B细胞因子1（ABF-1）在体外可结合该位点并抑制报告基因表达，但仅在存在LTA +80A等位基因的情况下。利用单倍型特异性染色质免疫沉淀技术，我们证实在体内ABF-1优先被招募至低表达等位基因。这些发现提供了一个分子模型，解释了转录抑制因子ABF-1如何通过等位基因特异性招募对LTA表达进行遗传调控。
