RNA-seq of different brain tissue areas of Trrap conditional knockout Mus musculus

The acetylation levels of histones and other proteins change during aging and have been linked to neurodegeneration. Here we show that deletion of the histone acetyltransferase (HAT) co-factor Trrap specifically impairs the function of the transcription factor Sp1, reduces its stability and causes a decrease in histone acetylation at Sp1 target genes. Modulation of Sp1 function by Trrap acts as a hub regulating multiple processes involved in neuron and neural stem cells function and maintenance including microtubule dynamics and the Wnt signaling pathway. Consistently, Trrap conditional mutants exhibit all hallmarks of neurodegeneration including dendrite retraction and axonal swellings, neuron death, astrogliosis, microglia activation, demyelination and decreased adult neurogenesis. Our results uncovered a novel functional network, essential to prevent neurodegeneration, and involving the specific regulation of Sp1 transcription factor and its downstream targets by Trrap-HAT.

组蛋白及其他蛋白质的乙酰化水平随衰老进程发生动态变化，且与神经退行性变密切相关。本研究证实，组蛋白乙酰转移酶（histone acetyltransferase, HAT）的辅因子Trrap缺失会特异性损伤转录因子Sp1的功能，降低其蛋白稳定性，并导致Sp1靶基因位点的组蛋白乙酰化水平显著下降。Trrap对Sp1功能的调控充当核心枢纽，调节神经元与神经干细胞的功能维持相关的多个生物学过程，涵盖微管动力学与Wnt信号通路等。与此一致，Trrap条件性敲除突变体展现出神经退行性变的全部典型特征，包括树突回缩、轴突肿胀、神经元死亡、星形胶质细胞增生、小胶质细胞激活、脱髓鞘以及成年神经发生水平降低。本研究结果揭示了一个全新的功能调控网络，该网络对于预防神经退行性变至关重要，其核心机制为Trrap-HAT复合物对Sp1转录因子及其下游靶基因的特异性调控。