Gui Yujuan, Thomas Mélanie H, Garcia Pierre, Karout Mona, Halder Rashi, Michelucci Alessandro, Kollmus Heike, Zhou Cuiqi, Melmed Shlomo, Schughart Klaus, Balling Rudi, Mittelbronn Michel, Nadeau Joseph H, Williams Robert W, Sauter Thomas, Buttini Manuel, Sinkkonen Lasse
Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg.
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.
Front Genet. 2020 Sep 23;11:566734. doi: 10.3389/fgene.2020.566734. eCollection 2020.
Dopaminergic neurons in the midbrain are of particular interest due to their role in diseases such as Parkinson's disease and schizophrenia. Genetic variation between individuals can affect the integrity and function of dopaminergic neurons but the DNA variants and molecular cascades modulating dopaminergic neurons and other cells types of ventral midbrain remain poorly defined. Three genetically diverse inbred mouse strains - C57BL/6J, A/J, and DBA/2J - differ significantly in their genomes (∼7 million variants), motor and cognitive behavior, and susceptibility to neurotoxins. To further dissect the underlying molecular networks responsible for these variable phenotypes, we generated RNA-seq and ChIP-seq data from ventral midbrains of the 3 mouse strains. We defined 1000-1200 transcripts that are differentially expressed among them. These widespread differences may be due to altered activity or expression of upstream transcription factors. Interestingly, transcription factors were significantly underrepresented among the differentially expressed genes, and only one transcription factor, , showed significant differences between all three strains. The changes in expression were accompanied by consistent alterations in histone H3 lysine 4 trimethylation at transcription start site. The ventral midbrain transcriptome of 3-month-old C57BL/6J congenic mutants was only modestly altered, but shifted toward that of A/J and DBA/2J in 9-month-old mice. Principle component analysis (PCA) identified the genes underlying the transcriptome shift and deconvolution of these bulk RNA-seq changes using midbrain single cell RNA-seq data suggested that the changes were occurring in several different cell types, including neurons, oligodendrocytes, and astrocytes. Taken together, our results show that contributes to gene regulatory variation between mouse strains and influences mouse midbrain transcriptome during aging.
由于中脑多巴胺能神经元在帕金森病和精神分裂症等疾病中所起的作用，它们备受关注。个体之间的基因变异会影响多巴胺能神经元的完整性和功能，但调节多巴胺能神经元及腹侧中脑其他细胞类型的DNA变异和分子级联反应仍不清楚。三种基因不同的近交系小鼠——C57BL/6J、A/J和DBA/2J——在基因组（约700万个变异）、运动和认知行为以及对神经毒素的易感性方面存在显著差异。为了进一步剖析导致这些可变表型的潜在分子网络，我们从这三种小鼠品系的腹侧中脑生成了RNA测序和染色质免疫沉淀测序数据。我们定义了1000 - 1200个在它们之间差异表达的转录本。这些广泛的差异可能是由于上游转录因子的活性或表达改变所致。有趣的是，转录因子在差异表达基因中显著缺失，并且只有一种转录因子在所有三个品系之间表现出显著差异。该转录因子表达的变化伴随着其转录起始位点处组蛋白H3赖氨酸4三甲基化的一致改变。3个月大的C57BL/6J同源突变体的腹侧中脑转录组仅发生了适度改变，但在9个月大的小鼠中向A/J和DBA/2J的转录组转变。主成分分析（PCA）确定了转录组转变背后的基因，并且使用中脑单细胞RNA测序数据对这些大量RNA测序变化进行去卷积分析表明，这些变化发生在几种不同的细胞类型中，包括神经元、少突胶质细胞和星形胶质细胞。综上所述,我们的结果表明该转录因子导致了小鼠品系间的基因调控变异，并在衰老过程中影响小鼠中脑转录组。
