Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore.
EMBO J. 2013 Apr 3;32(7):938-53. doi: 10.1038/emboj.2013.31. Epub 2013 Mar 8.
How regulatory information is encoded in the genome is poorly understood and poses a challenge when studying biological processes. We demonstrate here that genomic redistribution of Oct4 by alternative partnering with Sox2 and Sox17 is a fundamental regulatory event of endodermal specification. We show that Sox17 partners with Oct4 and binds to a unique 'compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at 'canonical' binding sites. The distinct selection of binding sites by alternative Sox/Oct partnering is underscored by our demonstration that rationally point-mutated Sox17 partners with Oct4 on pluripotency genes earmarked by the canonical Sox/Oct motif. In an endodermal differentiation assay, we demonstrate that the compressed motif is required for proper expression of endodermal genes. Evidently, Oct4 drives alternative developmental programs by switching Sox partners that affects enhancer selection, leading to either an endodermal or pluripotent cell fate. This work provides insights in understanding cell fate transcriptional regulation by highlighting the direct link between the DNA sequence of an enhancer and a developmental outcome.
调控信息在基因组中是如何编码的，目前人们对此知之甚少，这给研究生物过程带来了挑战。我们在这里证明，Oct4 通过与 Sox2 和 Sox17 的替代结合在基因组上的重新分布是内胚层特化的基本调控事件。我们表明 Sox17 与 Oct4 结合，并与一个独特的“压缩”Sox/Oct 基序结合，该基序标记内胚层基因。这与多能性状态形成对比，在多能性状态下，Oct4 选择性地与“经典”结合位点的 Sox2 结合。通过替代 Sox/Oct 结合的不同结合位点选择，我们通过证明合理的定点突变 Sox17 与由经典 Sox/Oct 基序标记的多能性基因上的 Oct4 结合得到了强调。在肠内胚层分化测定中，我们证明压缩基序是内胚层基因正确表达所必需的。显然，Oct4 通过切换 Sox 伴侣来驱动替代的发育程序，从而影响增强子选择，导致内胚层或多能细胞命运。这项工作通过突出增强子的 DNA 序列与发育结果之间的直接联系，为理解细胞命运转录调控提供了新的思路。
