Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network

The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. However, it remains unclear whether components of these networks functionally interact and if so, what factors mediate such interactions. Here we show that WD-repeat protein-5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a novel regulator of ES cell self-renewal. We demonstrate that Wdr5, an ‘effector’ of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. In concordance, genome-wide ChIP-Seq and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. We show that the Oct4-Sox2-Nanog circuitry cooperates with trxG for transcriptional activation of key self-renewal regulators. Furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. Collectively, these findings implicate an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming. Overall design: 7 Samples

胚胎干细胞（embryonic stem cell, ES）的转录调控与表观遗传网络，对于维持ES细胞自我更新至关重要。然而，目前仍不清楚这些网络的组分是否存在功能互作，若存在，又是哪些因子介导了此类互作。本研究证实，WD重复蛋白5（WD-repeat protein-5, Wdr5）——哺乳动物Trithorax（trxG）复合物的核心成员——与细胞未分化状态呈正相关，是ES细胞自我更新的新型调控因子。我们证明，作为H3K4甲基化的“效应因子”，Wdr5可与多能性转录因子Oct4发生相互作用。与之相符的是，全基因组染色质免疫共沉淀测序（ChIP-Seq）与转录组分析结果显示，Oct4与Wdr5存在重叠的基因调控功能。我们还发现，Oct4-Sox2-Nanog调控环路可与trxG复合物协同，激活关键自我更新调控因子的转录。此外，Wdr5的表达对于高效诱导多能干细胞（induced pluripotent stem, iPS细胞）的形成不可或缺。综上，这些研究结果揭示了一套由特定trxG成员介导的转录与表观遗传协同调控模型，该模型可维持ES细胞自我更新并参与体细胞重编程。整体实验设计：7个样本