Spadaro Paola A, Flavell Charlotte R, Widagdo Jocelyn, Ratnu Vikram S, Troup Michael, Ragan Chikako, Mattick John S, Bredy Timothy W
Queensland Brain Institute, The University of Queensland Australia, Brisbane, Queensland.
Garvan Institute of Medical Research, Darlinghurst, and St Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia.
Biol Psychiatry. 2015 Dec 15;78(12):848-59. doi: 10.1016/j.biopsych.2015.02.004. Epub 2015 Feb 11.
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 was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction 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 medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding RNA-directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays.
RNA sequencing 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 downregulation 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.
RNA 定向调控表观遗传过程最近已成为哺乳动物分化和发育的一个重要特征。大脑中这种调控系统的紊乱可能导致神经精神疾病的发生。
采用 RNA 测序来鉴定成年小鼠内侧前额叶皮质内长链非编码 RNA（lncRNA）的经验依赖性表达变化。通过实时定量聚合酶链反应验证转录本，并选择一个候选 lncRNA，Gomafu，进行进一步研究。通过在内侧前额叶皮质中进行反义寡核苷酸介导的基因敲低，随后进行行为训练和恐惧相关焦虑评估，在体内探索这种与精神分裂症相关的 lncRNA 的功能作用。通过染色质和 RNA 免疫沉淀试验研究 lncRNA 定向的基因表达表观遗传调控。
RNA 测序分析揭示了大量与神经可塑性和应激相关的基因表达变化，以及 lncRNA 的动态调控。特别是，我们检测到 Gomafu lncRNA 显著下调。我们的结果表明，Gomafu 在介导焦虑样行为中起作用，并表明这可能通过与多梳抑制复合体 1 的关键成员 BMI1 相互作用而发生，BMI1 调节与精神分裂症相关的基因β-晶状体蛋白（Crybb1）的表达。我们还证明了 Crybb1 在介导恐惧诱导的焦虑样行为中的新作用。
lncRNA 的经验依赖性表达在适应性行为的表观遗传调控中起重要作用，Gomafu 的紊乱可能与焦虑和神经精神疾病的发生有关。
