Laperriere David, Wang Tian-Tian, White John H, Mader Sylvie
Department of Biochemistry, University of Montreal, Montreal, Québec, H3C 3J7, Canada.
BMC Genomics. 2007 Jan 19;8:23. doi: 10.1186/1471-2164-8-23.
Nuclear receptors are hormone-regulated transcription factors whose signaling controls numerous aspects of development and physiology. Many receptors recognize DNA hormone response elements formed by direct repeats of RGKTCA motifs separated by 1 to 5 bp (DR1-DR5). Although many known such response elements are conserved in the mouse and human genomes, it is unclear to which extent transcriptional regulation by nuclear receptors has evolved specifically in primates.
We have mapped the positions of all consensus DR-type hormone response elements in the human genome, and found that DR2 motifs, recognized by retinoic acid receptors (RARs), are heavily overrepresented (108,582 elements). 90% of these are present in Alu repeats, which also contain lesser numbers of other consensus DRs, including 50% of consensus DR4 motifs. Few DR2s are in potentially mobile AluY elements and the vast majority are also present in chimp and macaque. 95.5% of Alu-DR2s are distributed throughout subclasses of AluS repeats, and arose largely through deamination of a methylated CpG dinucleotide in a non-consensus motif present in AluS sequences. We find that Alu-DR2 motifs are located adjacent to numerous known retinoic acid target genes, and show by chromatin immunoprecipitation assays in squamous carcinoma cells that several of these elements recruit RARs in vivo. These findings are supported by ChIP-on-chip data from retinoic acid-treated HL60 cells revealing RAR binding to several Alu-DR2 motifs.
These data provide strong support for the notion that Alu-mediated expansion of DR elements contributed to the evolution of gene regulation by RARs and other nuclear receptors in primates and humans.
核受体是受激素调节的转录因子，其信号传导控制着发育和生理的许多方面。许多受体识别由RGKTCA基序直接重复形成的DNA激素反应元件，这些重复序列之间间隔1至5个碱基对（DR1 - DR5）。尽管许多已知的此类反应元件在小鼠和人类基因组中是保守的，但尚不清楚核受体的转录调控在灵长类动物中具体进化到何种程度。
我们绘制了人类基因组中所有共有DR型激素反应元件的位置，发现视黄酸受体（RARs）识别的DR2基序大量存在（108,582个元件）。其中90%存在于Alu重复序列中，Alu重复序列中还含有数量较少的其他共有DR，包括50%的共有DR4基序。很少有DR2存在于潜在可移动的AluY元件中，绝大多数也存在于黑猩猩和猕猴中。95.5%的Alu - DR2分布在AluS重复序列的各个亚类中，并且主要是通过AluS序列中一个非共有基序中甲基化的CpG二核苷酸脱氨产生的。我们发现Alu - DR2基序位于许多已知视黄酸靶基因附近，并且通过鳞状癌细胞中的染色质免疫沉淀试验表明，其中一些元件在体内可招募RARs。视黄酸处理的HL60细胞的芯片杂交数据显示RAR与几个Alu - DR2基序结合，支持了这些发现。
这些数据为以下观点提供了有力支持，即Alu介导的DR元件扩增促进了灵长类动物和人类中RARs及其他核受体的基因调控进化。
