Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211, Kuopio, Finland.
Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia.
Acta Neuropathol Commun. 2018 Feb 27;6(1):17. doi: 10.1186/s40478-018-0519-z.
Traumatic brain injury (TBI) induces a wide variety of cellular and molecular changes that can continue for days to weeks to months, leading to functional impairments. Currently, there are no pharmacotherapies in clinical use that favorably modify the post-TBI outcome, due in part to limited understanding of the mechanisms of TBI-induced pathologies. Our system biology analysis tested the hypothesis that chronic transcriptomics changes induced by TBI are controlled by altered DNA-methylation in gene promoter areas or by transcription factors. We performed genome-wide methyl binding domain (MBD)-sequencing (seq) and RNA-seq in perilesional, thalamic, and hippocampal tissue sampled at 3 months after TBI induced by lateral fluid percussion in adult male Sprague-Dawley rats. We investigated the regulated molecular networks and mechanisms underlying the chronic regulation, particularly DNA methylation and transcription factors. Finally, we identified compounds that modulate the transcriptomics changes and could be repurposed to improve recovery. Unexpectedly, DNA methylation was not a major regulator of chronic post-TBI transcriptomics changes. On the other hand, the transcription factors Cebpd, Pax6, Spi1, and Tp73 were upregulated at 3 months after TBI (False discovery rate < 0.05), which was validated using digital droplet polymerase chain reaction. Transcription regulatory network analysis revealed that these transcription factors regulate apoptosis, inflammation, and microglia, which are well-known contributors to secondary damage after TBI. Library of Integrated Network-based Cellular Signatures (LINCS) analysis identified 118 pharmacotherapies that regulate the expression of Cebpd, Pax6, Spi1, and Tp73. Of these, the antidepressant and/or antipsychotic compounds trimipramine, rolipramine, fluspirilene, and chlorpromazine, as well as the anti-cancer therapies pimasertib, tamoxifen, and vorinostat were strong regulators of the identified transcription factors, suggesting their potential to modulate the regulated transcriptomics networks to improve post-TBI recovery.
创伤性脑损伤（TBI）会引起广泛的细胞和分子变化，这些变化可持续数天、数周甚至数月，导致功能障碍。目前，临床上没有任何药物治疗可以有效地改善 TBI 后的结果，部分原因是对 TBI 诱导的病变机制的理解有限。我们的系统生物学分析检验了这样一个假设，即 TBI 引起的慢性转录组变化是由基因启动子区域的 DNA 甲基化改变或转录因子控制的。我们在成年雄性 Sprague-Dawley 大鼠通过侧脑室液压冲击诱导 TBI 后 3 个月，对损伤灶周围、丘脑和海马组织进行了全基因组甲基结合域（MBD）测序（seq）和 RNA-seq。我们研究了调控慢性调节的分子网络和机制，特别是 DNA 甲基化和转录因子。最后，我们确定了可以调节转录组变化并可能被重新用于改善恢复的化合物。出乎意料的是，DNA 甲基化并不是慢性 TBI 后转录组变化的主要调节因子。另一方面，Cebpd、Pax6、Spi1 和 Tp73 转录因子在 TBI 后 3 个月上调（错误发现率<0.05），这通过数字液滴聚合酶链反应得到验证。转录调控网络分析表明，这些转录因子调节细胞凋亡、炎症和小胶质细胞，这些都是 TBI 后继发性损伤的众所周知的贡献者。基于整合网络的细胞特征（LINCS）文库分析确定了 118 种调节 Cebpd、Pax6、Spi1 和 Tp73 表达的药物疗法。在这些药物中，抗抑郁药和/或抗精神病药曲米帕明、罗利普兰、氟司匹林和氯丙嗪，以及抗癌疗法匹玛西特、他莫昔芬和伏立诺他，都是所鉴定的转录因子的强有力调节剂，这表明它们有可能调节受调控的转录组网络，以改善 TBI 后的恢复。
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