OCT4 Coordinates with WNT Signaling to Pre-pattern Chromatin at the SOX17 Locus during Human ES Cell Differentiation into Definitive Endoderm.
OCT4 Coordinates with WNT Signaling to Pre-pattern Chromatin at the SOX17 Locus during Human ES Cell Differentiation into Definitive Endoderm.
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DOI：
10.1016/j.stemcr.2015.08.014
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发表时间：
2015-10-13
影响因子：
5.9
通讯作者：
Gadue P
中科院分区：
文献类型：
--
作者：
Ying L;Mills JA;French DL;Gadue P
我们证明了多能基因OCT4通过Wnt信号调节分化。在体外分化的前24小时，人胚胎干细胞中Oct4的表达水平短暂增加，OCT4在SOX17和FOXA2等内胚层调节剂中的占有率增加。这种占有率的增加与PrC2复合体和抑制性组蛋白标记H3K27me3的丢失有关。OCT4在分化过程中的敲除抑制了中内胚层的形成和SOX17启动子上H3K27me3标记的去除，表明OCT4诱导PRC2复合体的去除。此外，OCT4和β-连环蛋白在分化过程中可以免疫共沉淀，并且需要WNT刺激才能增强OCT4的占位和从SOX17启动子中失去PRC2复合体。综上所述，我们的研究表明，OCT4，一个多能性的主要调节者，也可能与Wnt信号合作，通过在内胚层启动子上预先形成表观遗传标记来驱动内胚层的诱导。在ES细胞分化早期，OCT4在内胚层基因的占有率增加PRC2复合体在分化过程中从内胚层基因的OCT4位点丢失OCT4与β-连环蛋白在ES细胞分化过程中OCT4和WNT都是诱导中胚层所必需的在本文中，Gadue及其同事证明OCT4与Wnt信号协同作用调节特定的内胚层基因的表观遗传标记在分化开始后24小时内，为最终的表达做好准备。这项研究表明，一种被广泛描述的多能性调节因子OCT4也可以帮助引导下游分化。
We demonstrate that the pluripotency gene OCT4 has a role in regulating differentiation via Wnt signaling. OCT4 expression levels in human embryonic stem cells increases transiently during the first 24 hr of in vitro differentiation, with OCT4 occupancy increasing at endoderm regulators such as SOX17 and FOXA2. This increased occupancy correlates with loss of the PRC2 complex and the inhibitory histone mark H3K27me3. Knockdown of OCT4 during differentiation inhibits mesendoderm formation and removal of the H3K27me3 mark from the SOX17 promoter, suggesting that OCT4 acts to induce removal of the PRC2 complex. Furthermore, OCT4 and β-catenin can be co-immunoprecipitated upon differentiation, and Wnt stimulation is required for the enhanced OCT4 occupancy and loss of the PRC2 complex from the SOX17 promoter. In conclusion, our study reveals that OCT4, a master regulator of pluripotency, may also collaborate with Wnt signaling to drive endoderm induction by pre-patterning epigenetic markers on endodermal promoters. OCT4 occupancy increases at endoderm genes early in ES cell differentiation The PRC2 complex is lost from OCT4 sites on endoderm genes during differentiation OCT4 associates with β-catenin during ES cell differentiation OCT4 and Wnt are both required for mesendoderm induction In this article, Gadue and colleagues show that OCT4 in collaboration with WNT signaling acts to modulate epigenetic marks at definitive endoderm genes as little as 24 hr after differentiation initiation, priming them for eventual expression. This study demonstrates that a well-described regulator of pluripotency, OCT4, can also help direct downstream differentiation.