DNA-dependent formation of transcription factor pairs alters their binding specificity
DNA-dependent formation of transcription factor pairs alters their binding specificity
复制标题
DOI：
10.1038/nature15518
复制
发表时间：
2015-11-19
期刊：
影响因子：
64.8
通讯作者：
Taipale, Jussi
中科院分区：
文献类型：
--
作者：
Jolma, Arttu;Yin, Yimeng;Taipale, Jussi
基因表达受转录因子的调节，转录因子是识别短DNA序列基序(1-3)的蛋白质。这样的序列在人类基因组中非常常见，基因表达特异性的一个重要决定因素是多个TF与紧密定位的基序(4-6)的协同结合。然而，DNA结合的转录因子之间的相互作用还没有得到系统的表征。为了鉴定与DNA协同结合的Tf对，并表征它们的间距和取向偏好，我们对9,400个Tf-Tf-DNA相互作用进行了连续的亲和纯化系统进化指数法(CAP-SELEX)分析。这一分析揭示了315个Tf-Tf相互作用识别618个异二聚体基序，其中大部分以前没有被描述过。观察到的协作性在来自不同结构家族的TF之间混杂发生。对Tf对的结构分析，包括与其识别位点结合的Meis1和DLX3的新晶体结构，表明Tf之间的相互作用主要由DNA介导。大多数确定的Tf对位点涉及单个Tf识别基序之间的大量重叠，并导致识别与单个Tf基序明显不同的复合位点。综上所述，我们的结果表明，DNA分子通常在定义基因调控词典的合作相互作用中发挥积极作用。
Gene expression is regulated by transcription factors (TFs), proteins that recognize short DNA sequence motifs(1-3). Such sequences are very common in the human genome, and an important determinant of the specificity of gene expression is the cooperative binding of multiple TFs to closely located motifs(4-6). However, interactions between DNA-bound TFs have not been systematically characterized. To identify TF pairs that bind cooperatively to DNA, and to characterize their spacing and orientation preferences, we have performed consecutive affinity-purification systematic evolution of ligands by exponential enrichment (CAP-SELEX) analysis of 9,400 TF-TF-DNA interactions. This analysis revealed 315 TF-TF interactions recognizing 618 heterodimeric motifs, most of which have not been previously described. The observed cooperativity occurred promiscuously between TFs from diverse structural families. Structural analysis of the TF pairs, including a novel crystal structure of MEIS1 and DLX3 bound to their identified recognition site, revealed that the interactions between the TFs were predominantly mediated by DNA. Most TF pair sites identified involved a large overlap between individual TF recognition motifs, and resulted in recognition of composite sites that were markedly different from the individual TF's motifs. Together, our results indicate that the DNA molecule commonly plays an active role in cooperative interactions that define the gene regulatory lexicon.