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An expansive human regulatory lexicon encoded in transcription factor footprints

机译:在转录因子足迹中编码的膨胀人类调节词典

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摘要

Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNaseI, leaving nucleotide-resolution footprints. Using genomic DNaseI footprinting across 41 diverse cell and tissue types, we detected 45 million factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNaseI cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50 base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation, and pluripotency.
机译:调节因子与基因组DNA的结合可保护基础序列免受DNaseI的切割,从而留下核苷酸分辨率的印迹。使用横跨41种不同细胞和组织类型的基因组DNaseI足迹,我们在调节区内检测到4500万个因子占用事件,代表与840万个不同的短序列元件的差异结合。在这里,我们显示了这个小的基因组序列小室,大约是外显子组大小的两倍,编码了DNA结合蛋白的保守识别序列的扩展曲目,几乎使人类顺式调节词典的大小增加了一倍。我们发现影响等位基因染色质状态的遗传变异集中在脚印中,并且优先保护这些元素免受DNA甲基化的影响。高分辨率DNaseI裂解模式反映了核苷酸水平的进化保守性,并跟踪了蛋白质-DNA界面的晶体学形貌,表明转录因子结构已进化性地印在人类基因组序列上。我们确定了一个定型的50个碱基对的足迹,该足迹精确地定义了成千上万的人类启动子内的转录本起始位点。最后,我们描述了一系列在序列和功能上均高度保守的新型调节因子识别基序,并展示了细胞选择性占用模式,该模式与发育,分化和多能性的主要调控因子非常相似。

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