Transcriptome Analysis of the Cerebellum of Mice Fed a Manganese-Deficient Diet.
Transcriptome Analysis of the Cerebellum of Mice Fed a Manganese-Deficient Diet.
复制标题
DOI：
10.3389/fgene.2020.558725
复制
发表时间：
2020
影响因子：
3.7
通讯作者：
Iwase S
中科院分区：
文献类型：
--
作者：
Seo YA;Choi EK;Aring L;Paschall M;Iwase S
锰（Mn）主要通过饮食获得，是大脑功能和发育所必需的。流行病学研究发现，低水平和高水平的锰与儿童神经发育受损之间存在关联。最近的遗传学研究表明，先天性锰缺乏症患者表现出严重的精神残疾和大脑和小脑萎缩。虽然锰对基因表达的影响已开始得到重视，但在脊椎动物中锰依赖的基因表达仍有待探索。本研究的目的是使用小鼠模型来确定低锰饮食对脑金属水平和基因表达的影响。我们通过对低锰或正常锰饮食小鼠小脑的RNA-seq分析，在全基因组范围内询问了锰缺乏小鼠大脑中的基因表达变化。结果表明，与正常小脑相比，缺锰小脑有137个基因表达差异（Padj < 0.05）。锰缺乏小鼠显示下调的关键途径涉及“粘着斑”，“神经活性配体-受体相互作用”，和“精氨酸-细胞因子受体相互作用”和上调的“单纯疱疹病毒1型感染”，“剪接体”，和“FoxO信号通路”。反应组通路分析鉴定了剪接相关通路和转录相关通路的上调，以及“碳水化合物代谢”、“细胞外基质组织”和“脂肪酸代谢”反应组的下调。剪接相关途径的反复鉴定表明，锰缺乏导致剪接机制的上调和多种生物学途径的下调。
Manganese (Mn), primarily acquired through diet, is required for brain function and development. Epidemiological studies have found an association between both low and high levels of Mn and impaired neurodevelopment in children. Recent genetic studies have revealed that patients with congenital Mn deficiency display severe psychomotor disability and cerebral and cerebellar atrophy. Although the impact of Mn on gene expression is beginning to be appreciated, Mn-dependent gene expression remains to be explored in vertebrate animals. The goal of this study was to use a mouse model to define the impact of a low-Mn diet on brain metal levels and gene expression. We interrogated gene expression changes in the Mn-deficient mouse brain at the genome-wide scale by RNA-seq analysis of the cerebellum of mice fed low or normal Mn diets. A total of 137 genes were differentially expressed in Mn-deficient cerebellums compared with Mn-adequate cerebellums (Padj < 0.05). Mn-deficient mice displayed downregulation of key pathways involved with “focal adhesion,” “neuroactive ligand-receptor interaction,” and “cytokine-cytokine receptor interaction” and upregulation of “herpes simplex virus 1 infection,” “spliceosome,” and “FoxO signaling pathway.” Reactome pathway analysis identified upregulation of the splicing-related pathways and transcription-related pathways, as well as downregulation of “metabolism of carbohydrate,” and “extracellular matrix organization,” and “fatty acid metabolism” reactomes. The recurrent identifications of splicing-related pathways suggest that Mn deficiency leads to upregulation of splicing machineries and downregulation of diverse biological pathways.