Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.
Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.
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DOI：
10.1016/j.biopsych.2015.02.004
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发表时间：
2015-12-15
影响因子：
10.6
通讯作者：
Bredy TW
中科院分区：
文献类型：
--
作者：
Spadaro PA;Flavell CR;Widagdo J;Ratnu VS;Troup M;Ragan C;Mattick JS;Bredy TW
近年来，RNA对表观遗传过程的调控已成为哺乳动物分化和发育的重要特征。大脑中这一调节系统的紊乱可能会导致神经精神障碍的发展。RNA测序(RNA-seq)用于确定成年小鼠内侧前额叶皮质(MPFC)中长非编码RNA(LncRNAs)经验依赖性表达的变化。转录本通过实时定量聚合酶链式反应进行验证，并选择了候选的LncRNA，Gomafu，用于进一步研究。通过反义寡核苷酸介导的mPFC基因敲除，然后进行行为训练和恐惧相关焦虑的评估，在体内探索这种与精神分裂症相关的lncRNA的功能作用。用染色质和RNA免疫沉淀法研究了LncRNA对基因表达的表观遗传调控。RNA-seq分析揭示了与神经可塑性和应激相关的大量基因表达的变化，以及lncRNAs的动态调节。特别是，我们检测到Gomafu lncRNA显著下调。我们的结果显示，Gomafu在调节焦虑样行为方面发挥了作用，并表明这可能是通过与多梳抑制复合体1的关键成员BMI1相互作用而发生的，BMI1调节精神分裂症相关基因β晶体蛋白(Crbb1)的表达。我们还展示了Crbb1在调节恐惧诱导的焦虑样行为中的一个新角色。经验依赖的lncRNAs的表达在适应行为的表观遗传调控中起着重要作用，Gomafu的扰动可能与焦虑和神经精神障碍的发展有关。
RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders. RNA sequencing (RNA-seq) was used to identify changes in the experience-dependent expression of long non-coding RNAs (lncRNAs) within the medial prefrontal cortex (mPFC) of adult mice. Transcripts were validated by real-time quantitative PCR and a candidate lncRNA, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncRNA was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the mPFC, followed by behavioral training and assessment of fear-related anxiety. LncRNA-directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays. RNA-seq analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncRNAs. In particular, we detected a significant down-regulation of Gomafu lncRNA. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior, and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior. Experience-dependent expression of lncRNAs plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders.