Engaging the nucleosome Cell identity is defined by gene expression patterns that are established through the binding of specific transcription factors. However, nucleosomal units limit access of transcription factors to specific DNA motifs within the mammalian genome. To study how transcription factors bind such chromatinized, nucleosome-embedded motifs, Michael et al. focused on the pluripotency factors OCT4 and SOX2. They systematically quantified the relative affinities of these factors at different motif positions throughout the nucleosome, enabling structure determination of OCT4-SOX2–bound nucleosomes by cryo–electron microscopy. OCT4 and SOX2 bound cooperatively to strengthen DNA-binding affinity and resulted in DNA distortions that destabilized the nucleosome. This analysis reveals position-dependent binding modes that were validated in vivo, providing insights on how transcription factors read out chromatinized motifs. Science, this issue p. 1460 Site-specific nucleosome engagement by pluripotency factors reveals how transcription factors distort nucleosomes at chromatinized motifs. Transcription factors (TFs) regulate gene expression through chromatin where nucleosomes restrict DNA access. To study how TFs bind nucleosome-occupied motifs, we focused on the reprogramming factors OCT4 and SOX2 in mouse embryonic stem cells. We determined TF engagement throughout a nucleosome at base-pair resolution in vitro, enabling structure determination by cryo–electron microscopy at two preferred positions. Depending on motif location, OCT4 and SOX2 differentially distort nucleosomal DNA. At one position, OCT4-SOX2 removes DNA from histone H2A and histone H3; however, at an inverted motif, the TFs only induce local DNA distortions. OCT4 uses one of its two DNA-binding domains to engage DNA in both structures, reading out a partial motif. These findings explain site-specific nucleosome engagement by the pluripotency factors OCT4 and SOX2, and they reveal how TFs distort nucleosomes to access chromatinized motifs.

中文翻译：

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核小体上 OCT4-SOX2 基序读出的机制

参与核小体细胞身份由通过特定转录因子结合建立的基因表达模式定义。然而，核小体单元限制了转录因子对哺乳动物基因组内特定 DNA 基序的访问。为了研究转录因子如何结合这种染色质化的、核小体嵌入的基序，Michael 等人。专注于多能性因子 OCT4 和 SOX2。他们系统地量化了这些因子在整个核小体不同基序位置的相对亲和力，从而能够通过冷冻电子显微镜确定 OCT4-SOX2 结合的核小体的结构。OCT4 和 SOX2 协同结合以增强 DNA 结合亲和力，并导致 DNA 扭曲，使核小体不稳定。该分析揭示了在体内得到验证的位置依赖性结合模式，提供了有关转录因子如何读出染色质基序的见解。科学，这个问题 p。1460 多能性因子对位点特异性核小体的参与揭示了转录因子如何在染色质化基序处扭曲核小体。转录因子 (TF) 通过染色质调节基因表达，其中核小体限制 DNA 进入。为了研究 TF 如何结合核小体占据的基序，我们专注于小鼠胚胎干细胞中的重编程因子 OCT4 和 SOX2。我们在体外以碱基对分辨率确定了整个核小体中的 TF 参与，从而能够通过冷冻电子显微镜在两个首选位置确定结构。根据基序位置，OCT4 和 SOX2 会不同程度地扭曲核小体 DNA。在一个位置，OCT4-SOX2 从组蛋白 H2A 和组蛋白 H3 中去除 DNA；然而，在倒置基序中，TF 仅诱导局部 DNA 扭曲。OCT4 使用其两个 DNA 结合域中的一个在两个结构中与 DNA 结合，读出部分基序。这些发现解释了多能性因子 OCT4 和 SOX2 的位点特异性核小体参与，并且它们揭示了 TF 如何扭曲核小体以获取染色质基序。