Lawton Abigail, Morgan Caroline R, Schreiner Caleb R, Schreiner Chris G, Baumann Jacqueline, Upchurch Britton, Xu Feifan, Price Michael S, Isaacs Gary D
Department of Biology and Chemistry, Liberty University, Lynchburg, VA, United States.
Department of Molecular and Cellular Science, Liberty University College of Osteopathic Medicine, Lynchburg, VA, United States.
Front Nutr. 2020 Nov 12;7:574730. doi: 10.3389/fnut.2020.574730. eCollection 2020.
Short-term folate deficiency has been linked to cognitive defects. Given folate's role in regulating nucleotide synthesis and DNA and histone methylation, these changes are often linked to altered gene expression and might be controlled by specific regulatory networks. In our study we examined the effects of folic acid (FA) deficient or replete diets in mice, containing either no source of folate or normal FA intake, beginning post-weaning and persisting through the end of adult life at 18 months. Our goal was to assess levels of cognition in these mice using the novel object test and then connect the cognitive results to genetic changes. FA deficient mice showed significant memory impairment compared to control counterparts beginning at 5 months and persisting through 17 months, as determined by the novel object test. These deficits were associated with 363 significantly downregulated and 101 significantly upregulated genes in the deficient condition compared to the control condition in microarray analysis of hippocampal tissue. Many of these gene expression changes were determined to be specific to the hippocampus. Significant ontological categories for differential genes included nucleotide regulation, ion channel activity, and MAPK signaling; while some of these categories contain genes previously mapped to cognitive decline, other genes have not previously been associated with cognition. To determine proteins possibly involved in regulation of these genes, we performed bioinformatics analysis and found enriched motifs of for MafB and Zfp410 binding sites. These genes and enriched motifs may represent targets for treatment or investigation of memory-related diseases.
短期叶酸缺乏与认知缺陷有关。鉴于叶酸在调节核苷酸合成以及DNA和组蛋白甲基化方面的作用，这些变化通常与基因表达改变有关，并且可能受特定调控网络的控制。在我们的研究中，我们从断奶后开始，持续到18个月成年期结束，研究了叶酸（FA）缺乏或充足饮食对小鼠的影响，饮食中分别不含叶酸来源或正常FA摄入量。我们的目标是使用新物体测试评估这些小鼠的认知水平，然后将认知结果与基因变化联系起来。通过新物体测试确定，与对照小鼠相比，FA缺乏的小鼠从5个月开始到17个月持续表现出显著的记忆障碍。在海马组织的微阵列分析中，与对照条件相比，在缺乏状态下这些缺陷与363个显著下调和101个显著上调的基因有关。这些基因表达变化中的许多被确定为海马体特有的。差异基因的重要本体类别包括核苷酸调节、离子通道活性和MAPK信号传导；虽然这些类别中的一些包含先前已定位到认知衰退的基因，但其他基因以前尚未与认知相关联。为了确定可能参与这些基因调控的蛋白质，我们进行了生物信息学分析，发现了MafB和Zfp410结合位点的富集基序。这些基因和富集基序可能代表与记忆相关疾病治疗或研究的靶点。
