Molecular Cell Biology, Institute I for Anatomy, University of Cologne Medical School, Cologne, Germany
Cluster of Excellence-Cellular Stress Response in Aging-Associated Diseases (CECAD), Cologne, Germany.
EMBO J. 2018 Aug 15;37(16). doi: 10.15252/embj.201798659. Epub 2018 Jul 11.
Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc as regulators of genes required for neuroblast maintenance. Knockdown of Tip60 complex members results in loss of cortical polarity, symmetric neuroblast division, and premature differentiation through nuclear entry of the transcription factor Prospero. We found that aPKC is the key target gene of Myc and the Tip60 complex subunit Domino in regulating neuroblast polarity. Our transcriptome analysis further showed that Domino regulates the expression of mitotic spindle genes previously identified as direct Myc targets. Our findings reveal an evolutionarily conserved functional link between Myc, the Tip60 complex, and the molecular network controlling cell polarity and asymmetric cell division.
干细胞建立皮层极性并进行不对称分裂，从而维持自身和产生分化的后代细胞。几种染色质修饰物已被鉴定为哺乳动物多能干细胞中的干性因子，但这些因子是否控制干细胞极性和不对称分裂尚未得到研究。我们在称为神经母细胞的神经干细胞中解决了这个问题。我们确定了 Tip60 染色质重塑复合物及其相互作用伙伴 Myc 是调节神经母细胞维持所需基因的调节剂。Tip60 复合物成员的敲低导致皮质极性丧失、神经母细胞对称分裂和通过转录因子 Prospero 的核内进入过早分化。我们发现 aPKC 是 Myc 和调节神经母细胞极性的 Tip60 复合物亚基 Domino 的关键靶基因。我们的转录组分析进一步表明，Domino 调节有丝分裂纺锤体基因的表达，这些基因先前被鉴定为 Myc 的直接靶标。我们的研究结果揭示了 Myc、Tip60 复合物和控制细胞极性和不对称细胞分裂的分子网络之间的保守功能联系。
