The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA.
The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA.
Mol Cell. 2022 Sep 15;82(18):3398-3411.e11. doi: 10.1016/j.molcel.2022.06.029. Epub 2022 Jul 20.
Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, KLF, EGR, and ZBTB family members that recognize overlapping GC-rich sequences in all tissues analyzed. Knockouts and single-molecule tracking reveal that USFs impart accessibility to colocalized partners and increase their residence time. Mammalian cells have thus evolved a TF superfamily with overlapping DNA binding that facilitate chromatin accessibility.
调控元件通过招募转录因子 (TFs) 到特定基序来激活启动子。值得注意的是，TF-DNA 相互作用通常依赖于与共定位伙伴的协同作用，这表明存在潜在的顺式调控语法。为了探索哺乳动物中的 TF 协同作用，我们通过结合 TF 基序图谱、足迹、ChIP-seq、转录组和可及性，分析了约 500 个小鼠和人类原代细胞。我们发现了两组与大多数表达因子共定位的 TF，在层次聚类图谱中形成条纹。第一组包括谱系决定因子，它们广泛占据 DNA 元件，与它们在组织特异性转录中的关键作用一致。第二组称为通用条纹因子 (USFs)，包含约 30 个 SP、KLF、EGR 和 ZBTB 家族成员，它们在分析的所有组织中识别重叠的 GC 丰富序列。敲除和单分子跟踪揭示，USFs 赋予共定位伙伴可及性并增加其停留时间。因此，哺乳动物细胞已经进化出具有重叠 DNA 结合的 TF 超家族，这有助于染色质可及性。
