Allele-specific repression of lymphotoxin-α activated B cell factor-1
Allele-specific repression of lymphotoxin-α activated B cell factor-1
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DOI：
10.1038/ng1331
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发表时间：
2004-04-01
期刊：
影响因子：
30.8
通讯作者：
Kwiatkowski, DP
中科院分区：
文献类型：
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作者：
Knight, JC;Keating, BJ;Kwiatkowski, DP
人类LTA基因座的遗传变异，编码α-光氧素，与心肌梗死、哮喘和其他疾病的易感性有关。通过对该基因座的详细单倍型分析，我们确定了LTA + 80处的单核苷酸多态性（SNP）是人类B细胞产生LTA蛋白的主要预测因子。我们发现，活化的B细胞因子-1（ABF-1）在体外结合到该位点并抑制报告基因表达，但仅在LTA +80 A等位基因存在的情况下。使用单倍型特异性染色质免疫沉淀，我们证实，ABF-1优先招募到低生产等位基因在体内。这些发现提供了一个分子模型，LTA的表达可能是遗传调控的等位基因特异性招聘的转录抑制因子ABF-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.