Laboratório de Genética Animal e Humana, Departamento de Genética, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, USA.
Brain Behav. 2020 Dec;10(12):e01879. doi: 10.1002/brb3.1879. Epub 2020 Oct 23.
Gene prioritization approaches are useful tools to explore and select candidate genes in transcriptome studies. Knowing the importance of processes such as neuronal activity, intracellular signal transduction, and synapse plasticity to the development and maintenance of compulsive ethanol drinking, the aim of the present study was to explore and identify functional candidate genes associated with these processes in an animal model of inflexible pattern of ethanol intake. To do this, we applied a guilt-by-association approach, using the GUILDify and ToppGene software, in our previously published microarray data from the prefrontal cortex (PFC) and striatum of inflexible drinker mice. We then tested some of the prioritized genes that showed a tissue-specific pattern in postmortem brain tissue (PFC and nucleus accumbens (NAc)) from humans with alcohol use disorder (AUD). In the mouse brain, we prioritized 44 genes in PFC and 26 in striatum, which showed opposite regulation patterns in PFC and striatum. The most prioritized of them (i.e., Plcb1 and Prkcb in PFC, and Dnm2 and Lrrk2 in striatum) were associated with synaptic neuroplasticity, a neuroadaptation associated with excessive ethanol drinking. The identification of transcription factors among the prioritized genes suggests a crucial role for Irf4 in the pattern of regulation observed between PFC and striatum. Lastly, the differential transcription of IRF4 and LRRK2 in PFC and nucleus accumbens in postmortem brains from AUD compared to control highlights their involvement in compulsive ethanol drinking in humans and mice.
基因优先级方法是探索和选择转录组研究中候选基因的有用工具。鉴于神经元活动、细胞内信号转导和突触可塑性等过程对强迫性乙醇摄入的发展和维持的重要性，本研究旨在探索和鉴定与这些过程相关的功能性候选基因，以建立一种不可改变的乙醇摄入模式的动物模型。为此，我们使用 GUILDify 和 ToppGene 软件，应用关联有罪的方法，对我们之前发表的前额叶皮层（PFC）和纹状体的不可改变饮酒小鼠的微阵列数据进行分析。然后，我们在有酒精使用障碍（AUD）的人类死后脑组织（PFC 和伏隔核（NAc））中测试了一些表现出组织特异性模式的优先考虑的基因。在小鼠大脑中，我们在 PFC 中优先考虑了 44 个基因，在纹状体中优先考虑了 26 个基因，它们在 PFC 和纹状体中的调控模式相反。其中优先级最高的（即 PFC 中的 Plcb1 和 Prkcb，纹状体中的 Dnm2 和 Lrrk2）与突触神经可塑性有关，这是与过度乙醇摄入相关的神经适应。在优先考虑的基因中鉴定出转录因子表明，Irf4 在 PFC 和纹状体之间观察到的调控模式中起着关键作用。最后，与对照组相比，AUD 患者死后大脑 PFC 和伏隔核中 IRF4 和 LRRK2 的转录差异突出了它们在人类和小鼠强迫性乙醇摄入中的作用。
