Aberrant brain miRNA target and miRISC gene expression in the anx/anx anorexia mouse model

The anorexia mouse model, anx/anx, carries a spontaneous mutation not yet identified and homozygous mutants are characterized by anorexia-cachexia, growth failure and abnormal behavior, such as head weaving, hyperactivity, and ataxia. In order to test if miRNA machinery could influence the phenotype of these mice, RNA samples from mutant and wild type hypothalamus and cortex were hybridized to microarray chips based on LNA probes allowing the detection of 279 mouse miRNAs and to Agilent 44k chips to analyze the whole mRNA transcriptome. In anx/anx hypothalamus we found that predicted miRNA targets were preferentially upregulated in a lineally dependent manner according to the number of miRNA target sites in each mRNA (p = 10-139). Conversely, we observed that in anx/anx cortex mRNAs predicted to be targeted by miRNAs were preferentially downregulated (p < 10-74), suggesting a de-regulation of genes targeted by miRNAs in two brain areas in anx/anx mice. A closer look to the mRNA transcriptome allowed us to identify upregulation of five miRISC genes, including Dgcr8 and Fmr1, and Ago2, which were later confirmed by Real Time PCR. The results suggest that miRNA machinery might be impaired in anx/anx mice and propose its involvement in inflammatory/cancer-associated anorexia-cachexia. The data also support the previously reported link between miRNA machinery and ataxia. Further functional studies and the cloning of the anx gene should be done in order to elucidate the causality of miRNA machinery and miRNA target de-regulation, its relation with the anx/anx phenotype and to propose this mouse as a model for miRNA research. Total RNA expression profile comparison between 3 pairs of anx/anx mice and wild type littermates in brain neocortex. MicroRNA expression profile comparison between 3 pairs of anx/anx mice and wild type littermates in brain neocortex.本数据集针对anx/anx厌食症小鼠模型（anorexia mouse model, anx/anx）展开研究，该模型携带尚未明确的自发突变，其纯合突变体表现出厌食-恶病质、生长发育迟缓以及头部摇摆、活动亢进、共济失调等异常行为。为验证微小RNA（miRNA）加工机制是否可影响该类小鼠的表型，研究人员将突变型与野生型小鼠的下丘脑及皮层RNA样本，与基于锁核酸（LNA）探针的微阵列芯片进行杂交（该芯片可检测279种小鼠miRNA），同时采用安捷伦（Agilent）44k芯片分析全mRNA转录组。在anx/anx小鼠下丘脑中，研究人员发现预测受miRNA靶向的mRNA呈线性依赖方式优先上调，且上调幅度与每条mRNA上的miRNA靶位点数量正相关（p=10^-139）。反之，在anx/anx小鼠皮层中，预测受miRNA靶向的mRNA则呈现优先下调（p<10^-74），这表明anx/anx小鼠的两个脑区中，受miRNA靶向的基因均存在表达失调现象。进一步对mRNA转录组的分析显示，5种miRNA诱导沉默复合物（miRISC）相关基因出现上调，包括Dgcr8、Fmr1及Ago2，该结果后续通过实时荧光定量PCR（Real Time PCR）得以验证。研究结果提示，anx/anx小鼠的miRNA加工机制可能存在损伤，并暗示其与炎症/癌症相关厌食-恶病质存在关联。本数据集同时支持此前报道的miRNA加工机制与共济失调之间的关联。为阐明miRNA加工机制及miRNA靶基因表达失调的因果关系、其与anx/anx表型的关联，并将该小鼠模型作为miRNA研究的工具模型，后续需开展更多功能学研究并克隆anx基因。本数据集包含3对anx/anx小鼠与野生型同窝小鼠的大脑新皮层总RNA表达谱对比数据，以及3对anx/anx小鼠与野生型同窝小鼠的大脑新皮层miRNA表达谱对比数据。