Meert Lize, Pelicano de Almeida Mariana, Dekker Mike R, Dekkers Dick H W, Nowosad Karol, Huylebroeck Danny, van den Hout Mirjam, Ozgür Zeliha, van IJcken Wilfred F J, Demmers Jeroen, Fornerod Maarten, Poot Raymond A
Department of Cell Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
Center for Proteomics, Erasmus MC, 3015 CN Rotterdam, the Netherlands.
iScience. 2025 Feb 12;28(3):111978. doi: 10.1016/j.isci.2025.111978. eCollection 2025 Mar 21.
Mutations in ATP-dependent chromatin remodeler CHD8 cause one of the most frequent monogenetic forms of autism and are associated with brain overgrowth. Nevertheless, the activities of CHD8 in autism-relevant cell types are still poorly understood. Here, we purify the CHD8 protein from human neural stem cells and determine its interaction partners using mass spectrometry. We identify the TRRAP complex, a coactivator of MYC and E2F transcription factors, as a prominent CHD8 interaction partner. CHD8 colocalizes genome-wide with TRRAP and binds together at MYC and E2F target gene promoters in human neural stem cells. Depletion of CHD8 or TRRAP in human neural stem cells shows downregulation of MYC and E2F target genes as the most prominent gene-regulatory events. Depletion of CHD8 diminishes cell-cycle entry into S-phase. MYC and E2F transcription factors are established oncogenes and regulate cell growth. Our results link CHD8 to TRRAP in facilitating the regulation of MYC and E2F target genes in human neural stem cells.
ATP 依赖性染色质重塑因子 CHD8 的突变导致了最常见的单基因自闭症形式之一，并且与大脑过度生长有关。然而，CHD8 在与自闭症相关的细胞类型中的活性仍知之甚少。在这里，我们从人类神经干细胞中纯化了 CHD8 蛋白，并使用质谱法确定了其相互作用伙伴。我们鉴定出 TRRAP 复合物，它是 MYC 和 E2F 转录因子的共激活因子，是 CHD8 的一个重要相互作用伙伴。在全基因组范围内，CHD8 与 TRRAP 共定位，并在人类神经干细胞中的 MYC 和 E2F 靶基因启动子处结合在一起。在人类神经干细胞中耗尽 CHD8 或 TRRAP 会导致 MYC 和 E2F 靶基因的下调，这是最显著的基因调控事件。CHD8 的耗尽会减少细胞周期进入 S 期。MYC 和 E2F 转录因子是已确定的致癌基因，可调节细胞生长。我们的结果将 CHD8 与 TRRAP 联系起来，以促进对人类神经干细胞中 MYC 和 E2F 靶基因的调控。
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