The changes of the nuclear landscape upon stimulation of neuronal cells are dependent on the histone deacetylase HDAC1

Spatial chromatin organization is crucial for transcriptional regulation and might therefore be particularly dynamic in neurons since these terminally differentiated cells dramatically change their transcriptome in response to external stimuli. Here, we show that stimulation of neurons causes condensation of large chromatin domains. We find that this phenomenon is not only induced in rat hippocampal neurons cultured in vitro, but is also present in vivo in amygdala neurons of rats subjected to fear conditioning, and hippocampal neurons of animals subjected to kainate evoked seizures or High-Frequency Stimulation (HFS). The activity-induced chromatin condensation is an active, very rapid, and reversible process, that is independent of transcription and precedes the expression of Immediate Early Genes (IEG). It is accompanied by the redistribution of posttranslational modifications of histones, and rearrangements in the spatial organization of chromosome territories. Moreover, it leads to the reorganization of nuclear speckles and active domains located in their proximity. Finally, we find that neurons depleted of the histone deacetylase HDAC1 fail to condense chromatin upon stimulation, a phenomenon that can be fully reversed by the introduction of human HDAC1. Taken together, our results suggest that the HDAC1-dependent chromatin reorganization might constitute an important level of fine-tuning of transcriptional regulation in stimulated neurons.空间染色质组织（spatial chromatin organization）对转录调控至关重要，而神经元作为终末分化细胞可响应外界刺激并剧烈改变自身转录组，因此该过程在神经元中可能尤为动态。本研究证实，神经元受到刺激后会发生大型染色质结构域的凝缩。我们发现，这一现象不仅在体外培养的大鼠海马神经元中得以诱导，还存在于三类体内样本中：接受恐惧条件反射的大鼠杏仁核神经元、经红藻氨酸诱导癫痫发作的动物海马神经元，以及接受高频刺激（High-Frequency Stimulation, HFS）的动物海马神经元。这种活性诱导的染色质凝缩是一个主动、极为快速且可逆的过程，不依赖转录，且早于即刻早期基因（Immediate Early Genes, IEG）的表达。该过程伴随组蛋白翻译后修饰的重分布，以及染色体领地空间组织的重排。此外，它还会引发核斑及其邻近活性结构域的重构。最后，我们发现敲除组蛋白去乙酰化酶（histone deacetylase）HDAC1的神经元在受到刺激后无法发生染色质凝缩，而这一现象可通过导入人源HDAC1完全逆转。综合以上结果，我们认为依赖HDAC1的染色质重构或许是受刺激神经元中转录调控精细校准的关键环节。