脑衰老过程中长链非编码RNA对学习记忆相关基因的调控功能及机制

项目名称： 脑衰老过程中长链非编码RNA对学习记忆相关基因的调控功能及机制

项目编号： No.91540107

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 宋晓元

作者单位： 中国科学技术大学

项目金额： 85万元

中文摘要： 学习记忆功能减退是脑衰老早期指标之一，但机制不明。我们前期发现，在与学习记忆密切相关的脑海马区特异表达的lncRNA和mRNA几乎都在自然衰老的老年小鼠中显著上调。这些海马特异的mRNA与学习记忆及衰老密切相关，并与海马特异的lncRNA存在共表达关系。结合lncRNA与染色质构象对基因调控的协同作用，我们假设：lncRNA在脑衰老过程中参与形成年龄特异的染色质三维构象来共同调控学习记忆相关基因，这可能是脑衰老过程中学习记忆功能减退的重要分子基础之一。本项目将结合RNA-Seq和3D-DSL等技术检测海马区神经组织在小鼠青年和老年时lncRNA表达及染色质构象的变化、以及两者间形成的三维基因调控网络对脑衰老过程中学习记忆相关基因的表达调控，及其与小鼠学习记忆功能减退之间的因果关系，并探究其作用机制。本研究对揭示脑衰老分子机制有重要意义，并可能为延缓脑衰老以及防治脑衰老相关疾病提供新思路。

中文关键词： 长链非编码RNA；脑衰老；学习记忆相关基因；染色质相互作用；三维转录调控

英文摘要： Learning and memory impairment is one of the early phenotypes in brain aging, but the underlying mechanism is not clear. Our preliminary data showed that, in hippocampus which is closely related to learning and memory, hippocampus-specifically expressed lncRNAs and mRNAs were almost all significantly up-regulated in the natural aged mice. These specific mRNAs are closely related to learning and memory as well as senescence, and the expression of these specific lncRNAs is also closed related to the expression of the hippocampus-specific mRNAs. Combining with these data and the synergistic effect of lncRNAs and chromatin conformation on gene regulation, we hypothesize that lncRNAs are involved in the formation of age-specific chromatin three-dimensional conformation to regulate learning and memory related genes during brain aging process, which may be one of the key molecular bases for the impairment of learning and memory during brain aging. The project will use technologies such as RNA-Seq and 3D-DSL to detect the changes of lncRNAs’ expression and chromatin conformation, as well as the three-dimensional gene regulation networks formed based on the interactions between lncRNAs and chromatin conformation in learning and memory-dependent hippocampus from young and old mice. From which we will identify how they regulate learning and memory related genes, discover the causal relationship between this gene regulation and learning and memory impairment in mice brain aging process, and explore the functional mechanisms. This study is important to reveal the molecular mechanisms of brain aging, and may lead to new ideas for slowing down the aging process and for the prevention of brain aging related diseases.

英文关键词： long non-coding RNA;brain senescence;learning and memory related genes;chromatin interaction;three-dimensional transcriptional regulation