Laboratory Animal Research Center, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong, 510623, China.
Genes Genomics. 2020 Nov;42(11):1259-1265. doi: 10.1007/s13258-020-00996-8. Epub 2020 Sep 18.
Down syndrome (DS), caused by trisomy 21, is the most common human chromosomal disorder. Hippocampal abnormalities have been believed to be responsible for the DS developmental cognitive deficits. Cumulative evidences indicated that non-coding RNAs (ncRNAs) participated in brain development and function. Currently, few was known whether dysregulated ncRNAs existed in DS whether the dysregulated ncRNAs played important pathology roles in DS.
The purpose of this study was generating an overview map of the dysregulated ncRNAs in DS, including the microRNA (miRNA), long ncRNA (lncRNA) and circular RNA (circRNAs). DS mouse models are invaluable tools for further mechanism and therapy studies.
The well-studied DS mouse model Dp(16)1/Yey was used in this study as it contains the trisomy of the whole human chromosome 21 syntenic region on mouse chromosomes 16. Hippocampi were isolated from pups of seven-days-old. Libraries for miRNA, lncRNA and circRNAs were constructed separately, and the next generation sequencing method was utilized.
Differentially expressed (DE) miRNAs, lncRNAs and circRNAs were reported. Relative few regulating relationship were found between the DE miRNAs and DE mRNAs. LncRNAs originated from the trisomic regions expressed in clusters, but not all of them were 1.5-fold increased expressed. Dramatic DE circular RNAs were found in the DS hippocampus. The host genes of the DE circRNAs were enriched on functions which were well-known impaired in DS, e.g. long-term-potentiation, glutamatergic synapse, and GABAergic synapse.
We generated the first DS developmental hippocampal ncRNA transcriptome map. This work laid foundations for further investigations on role of ncRNAs in hippocampal functions.
唐氏综合征（DS）由 21 三体引起，是最常见的人类染色体疾病。海马异常被认为是导致 DS 发育性认知缺陷的原因。越来越多的证据表明，非编码 RNA（ncRNA）参与了大脑发育和功能。目前，尚不清楚 DS 是否存在失调的 ncRNA，以及失调的 ncRNA 是否在 DS 中发挥重要的病理作用。
本研究旨在生成 DS 中失调 ncRNA 的概述图谱，包括 microRNA（miRNA）、长链非编码 RNA（lncRNA）和环状 RNA（circRNA）。DS 小鼠模型是进一步机制和治疗研究的宝贵工具。
本研究使用了研究较为充分的 DS 小鼠模型 Dp（16）1/Yey，因为它包含了人类整条 21 号染色体在小鼠 16 号染色体上的同源区域的三倍体。从 7 天大的幼鼠中分离出海马体。分别构建了 miRNA、lncRNA 和 circRNA 文库，并利用下一代测序方法进行了分析。
报告了差异表达（DE）的 miRNA、lncRNA 和 circRNA。在 DE miRNA 和 DE mRNA 之间发现了相对较少的调节关系。来自三体区域的 lncRNA 以簇的形式表达，但并非所有 lncRNA 都表达增加了 1.5 倍。在 DS 海马体中发现了大量的 DE circRNA。DE circRNA 的宿主基因富集在 DS 中已知受损的功能上，如长时程增强、谷氨酸能突触和 GABA 能突触。
我们生成了首张 DS 发育性海马 ncRNA 转录组图谱。这项工作为进一步研究 ncRNA 在海马功能中的作用奠定了基础。
