Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level
Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level
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DOI：
10.1101/gr.089086.108
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发表时间：
2009-06-01
期刊：
影响因子：
7
通讯作者：
Vetrie, David
中科院分区：
文献类型：
--
作者：
Bruce, Alexander W.;Lopez-Contreras, Andres J.;Vetrie, David
人们对转录因子与哺乳动物基因组中同源DNA序列基序的体内结合的分子事件知之甚少。我们证明，在DNA序列基序的变化，结合转录抑制因子REST（NRSF）编码体内DNA结合亲和力层次，有助于调节功能的谱系特异性和发展计划的基本方式。首先，REST的规范序列基序促进强REST结合并控制所有细胞类型共有的REST靶标的功能类别，而非典型基序参与弱相互作用并控制那些细胞或组织特异性的靶标。第二，REST结合的变化与REST靶基因的表达和染色质构型的变化直接相关。第三，REST从其结合位点的清除也与RE1基序的变化有关。最后，也是最令人惊讶的是，弱REST结合位点存在于DNA序列中，这些DNA序列在进化过程中表现出最高水平的约束，从而促进了它们在维持组织特异性功能中的作用。这些关系从来没有在哺乳动物系统中的任何转录因子的报告。
The molecular events that contribute to, and result from, the in vivo binding of transcription factors to their cognate DNA sequence motifs in mammalian genomes are poorly understood. We demonstrate that variations within the DNA sequence motifs that bind the transcriptional repressor REST ( NRSF) encode in vivo DNA binding affinity hierarchies that contribute to regulatory function during lineage-specific and developmental programs in fundamental ways. First, canonical sequence motifs for REST facilitate strong REST binding and control functional classes of REST targets that are common to all cell types, whilst atypical motifs participate in weak interactions and control those targets, which are cellor tissue-specific. Second, variations in REST binding relate directly to variations in expression and chromatin configurations of REST's target genes. Third, REST clearance from its binding sites is also associated with variations in the RE1 motif. Finally, and most surprisingly, weak REST binding sites reside in DNA sequences that show the highest levels of constraint through evolution, thus facilitating their roles in maintaining tissue-specific functions. These relationships have never been reported in mammalian systems for any transcription factor.