Cell cycle dependence of neuroprogenitor fate determination regulated by Trrap-mediated histone acetylation

Epigenetic control of neural stem/progenitor cell fate is fundamental to achieve a fully brain architecture. Two intrinsic programs regulate neurogenesis, one by epigenetic-mediated gene transcription and another by cell cycle control. Whether and how these two are coordinated to determine temporally and spatially neural development remains unknown. Here we show that deletion of Trrap (Transcription translation associated protein), an essential cofactor for HAT (histone acetyltransferase), leads to severe brain atrophy due to a combination of cell death and a blockade of neuron production. Specifically, Trrap deletion forces differentiation of apical progenitor (AP) fate into basal progenitors (BP) and neurons thereby limiting the total neurogenic production. Despite Trrap's general role in transcriptional regulation, a genome-wide transcriptome analysis of neuroprogenitors identified the cell cycle regulators that are specifically affected by Trrap deletion. Furthermore, E2F-dependent recruitment of HAT and transcription factors to the promoter of cell cycle regulators is impaired in Trrap-deleted neuroprogenitors. Consistent with these molecular changes, Trrap deletion lengthens particularly G1 and S phases in APs in vivo. Therefore, our study reveals an essential and a distinct function of Trrap-HAT in regulation of cell cycle progression that is required for proper determination of neuroprogenitor fate. Determine gene transcriptions by comparing Trrap-deleted and wild type samples神经干细胞/祖细胞（neural stem/progenitor cell）命运的表观遗传调控（epigenetic control）对于构建完整大脑架构是必需的。调控神经发生（neurogenesis）的内在程序共有两种：其一为表观遗传介导的基因转录调控，其二为细胞周期调控。目前尚不明确这两种程序是否以及如何相互协同，从而在时空维度上调控神经发育。本研究发现，Trrap（转录翻译相关蛋白，Transcription translation associated protein）作为组蛋白乙酰转移酶（histone acetyltransferase, HAT）的必需辅因子，其缺失会因细胞死亡与神经元生成受阻共同导致严重的大脑萎缩。具体而言，Trrap缺失会促使顶端祖细胞（apical progenitor, AP）的命运向基底祖细胞（basal progenitor, BP）和神经元分化，进而减少总神经发生产量。尽管Trrap在转录调控中具有普遍功能，但对神经祖细胞（neuroprogenitor）的全基因组转录组分析显示，仅有细胞周期调控因子会被Trrap缺失特异性影响。此外，在Trrap缺失的神经祖细胞中，依赖E2F因子介导的组蛋白乙酰转移酶（HAT）与转录因子向细胞周期调控因子启动子区域的募集过程受到损伤。与这些分子变化一致，Trrap缺失会在体内显著延长顶端祖细胞（AP）的G1期与S期时长。综上，本研究揭示了Trrap-组蛋白乙酰转移酶在细胞周期进程调控中的必需且独特的功能，这一功能是神经祖细胞命运正确决定所必需。本研究通过对比Trrap缺失组与野生型（wild type）样本的基因转录组分析，明确了相关基因的转录差异。