干细胞分化过程中OCT4依赖SOX的基因组重新分布的结构基础。

Structural basis for the SOX-dependent genomic redistribution of OCT4 in stem cell differentiation.

作者信息

Merino Felipe, Ng Calista Keow Leng, Veerapandian Veeramohan, Schöler Hans Robert, Jauch Ralf, Cojocaru Vlad

机构信息

Computational Structural Biology Group, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Correnstrasse 40, 48149 Münster, Germany.

Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.

出版信息

Structure. 2014 Sep 2;22(9):1274-1286. doi: 10.1016/j.str.2014.06.014. Epub 2014 Aug 7.

DOI:10.1016/j.str.2014.06.014

PMID:25126959

Abstract

In pluripotent cells, OCT4 associates with SOX2 to maintain pluripotency or with SOX17 to induce primitive endoderm commitment. The OCT4-SOX2 and OCT4-SOX17 combinations bind mutually exclusive to two distinct composite DNA elements, known as the "canonical" and "compressed" motifs, respectively. The structural basis for the OCT4-SOX17 cooperativity is unknown. Whereas SOX17 has been engineered to replace SOX2 in the pluripotency circuitry, all generated SOX2 mutants have failed to act like SOX17. From molecular simulations, we revealed the OCT4-SOX17 interaction interface and elucidated the SOX-dependent motif preference of OCT4. Moreover, we designed a SOX2 mutant that we predicted and confirmed experimentally to bind cooperatively with OCT4 to the compressed motif. Ultimately, we found a strong correlation between the experimental and calculated relative cooperative-binding free energies of 12 OCT4-SOX-DNA complexes. Therefore, we validated the OCT4-SOX interfaces and demonstrated that in silico design of DNA-binding cooperativity is suitable for altering transcriptional circuitries.

摘要

在多能细胞中，OCT4与SOX2结合以维持多能性，或与SOX17结合以诱导原始内胚层定向分化。OCT4-SOX2和OCT4-SOX17组合分别与两个不同的复合DNA元件相互排斥结合，这两个元件分别称为“经典”和“压缩”基序。OCT4-SOX17协同作用的结构基础尚不清楚。尽管已设计出SOX17来替代多能性调控回路中的SOX2，但所有产生的SOX2突变体都未能表现出与SOX17相似的功能。通过分子模拟，我们揭示了OCT4-SOX17相互作用界面，并阐明了OCT4对SOX依赖的基序偏好。此外，我们设计了一种SOX2突变体，通过预测和实验证实它能与OCT4协同结合到压缩基序上。最终，我们发现12种OCT4-SOX-DNA复合物的实验和计算相对协同结合自由能之间存在很强的相关性。因此，我们验证了OCT4-SOX界面，并证明DNA结合协同性的计算机辅助设计适用于改变转录调控回路。