Mechanisms of OCT4-SOX2 motif readout on nucleosomes
Mechanisms of OCT4-SOX2 motif readout on nucleosomes
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DOI：
10.1126/science.abb0074
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发表时间：
2020-06-26
期刊：
影响因子：
56.9
通讯作者：
Thomae, Nicolas H.
中科院分区：
文献类型：
--
作者：
Michael, Alicia K.;Grand, Ralph S.;Thomae, Nicolas H.
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OCT 4和SOX 2。我们确定TF参与整个核小体在体外的碱基对分辨率，使结构测定冷冻电子显微镜在两个优选的位置。根据基序的位置，OCT 4和SOX 2差异扭曲核小体DNA。在一个位置，OCT 4-SOX 2从组蛋白H2 A和组蛋白H3中去除DNA;然而，在反向基序处，TF仅诱导局部DNA扭曲。OCT 4使用其两个DNA结合结构域中的一个与两种结构中的DNA结合，阅读部分基序。这些发现解释了多能性因子OCT 4和SOX 2的位点特异性核小体接合，并且它们揭示了TF如何扭曲核小体以访问染色质化的基序。
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.