Epigenetic reprogramming of cell identity in the rat primary neuron-glia cultures involves histone serotonylation

Epigenetic rearrangements can create a favorable environment for the intrinsic plasticity of brain cells, leading to cellular reprogramming into virtually any cell type through the induction of cell-specific transcriptional programs. In this study, we assessed how chromatin remodeling induced by broad-spectrum HDAC inhibitors affects cellular differentiation trajectories in rat primary neuron-glia cultures using a combination of transcriptomics, qPCR and cytochemistry. We described epigenetic regulation of transcriptional programs controlled by master transcription factors and neurotrophins in the context of neuronal and glial differentiation and evaluated the expression of representative cell-specific markers. The results obtained suggest that HDAC inhibitors reduce proliferative potential of cultured cells and induce transcriptomic changes associated with cell differentiation and specialization. Particularly, we revealed a significant upregulation of genes typically expressed in neuromodulatory neurons, and downregulation of genes expressed in glia and inhibitory neurons. Transcriptional changes were accompanied by continuous elevation of histone serotonylation levels in both neurons and glia. We assume that early appearance of the enhanced histone serotonylation marks, and the persistence of these changes over many hours in distinct brain cells may indicate that chromatin remodeling induced by histone serotonylation contributes to the maintainance of a new transcriptional programs associated with cellular reprogramming.表观遗传重排（epigenetic rearrangements）可为脑细胞的内在可塑性创造有利环境，通过诱导细胞特异性转录程序，促使细胞重编程为几乎所有细胞类型。本研究结合转录组学（transcriptomics）、qPCR与细胞化学（cytochemistry）分析，探究广谱组蛋白去乙酰化酶抑制剂（HDAC inhibitors）诱导的染色质重塑（chromatin remodeling）对大鼠原代神经元-胶质细胞培养物中细胞分化轨迹的影响。本研究描述了神经元与胶质细胞分化过程中，主转录因子（master transcription factors）与神经营养因子（neurotrophins）所调控的转录程序的表观遗传调控机制，并评估了代表性细胞特异性标志物的表达水平。研究结果表明，组蛋白去乙酰化酶抑制剂可降低培养细胞的增殖潜能，并诱导与细胞分化及特化相关的转录组学改变。尤为关键的是，本研究发现神经调节性神经元（neuromodulatory neurons）特异性表达的基因显著上调，而胶质细胞与抑制性神经元（inhibitory neurons）特异性表达的基因则显著下调。转录组学改变伴随神经元与胶质细胞中组蛋白血清素化（histone serotonylation）水平的持续升高。我们推测，增强的组蛋白血清素化标记的早期出现，以及这些变化在不同脑细胞中持续数小时的现象，或表明组蛋白血清素化介导的染色质重塑有助于维持与细胞重编程相关的新型转录程序。