Coding and Non-Coding RNA Abnormalities in Bipolar Disorder
Coding and Non-Coding RNA Abnormalities in Bipolar Disorder
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DOI：
10.3390/genes10110946
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发表时间：
2019-11-01
期刊：
影响因子：
3.5
通讯作者：
Veldink, Jan
中科院分区：
文献类型：
--
作者：
Luykx, Jurjen J.;Giuliani, Fabrizio;Veldink, Jan
双相情感障碍（BPD）的分子机制在很大程度上仍然未知。通过比较BPD患者与健康对照者的死后脑组织研究，发现了一组异质的可能与之相关的蛋白质编码rna。我们推测，BPD的发病机制不仅是编码的失调，还有多种类型的RNA（编码RNA、长链非编码RNA、环状RNA和/或选择性剪接）的失调。利用非聚腺苷化文库，我们对来自BPD患者和健康对照者的死后人类内侧额回组织进行了RNA测序。20个基因，其中一些先前未涉及BPD，差异表达（DE）。PCR验证和复制证实了这些DE基因的含义。功能性硅分析鉴定了血管生成、血管系统发育和组蛋白H3-K4去甲基化的富集。此外，10个lncRNA转录本存在差异表达。此外，检测到BPD中选择性剪接事件的总体数量增加，以及携带选择性剪接事件的基因数量增加。最后，研究人员描述了大量不受BPD影响的环状rna储存在脑组织中，而在BPD中，两种环状转录本cNEBL和cEPHA3的水平发生了改变。迄今为止与BPD无关的cEPHA3与中枢神经系统的发育过程有关。虽然我们没有对非编码RNA的研究结果进行复制分析，但我们的研究结果表明，BPD中的RNA失调并不局限于编码区域，这为未来的药理学研究和生物标志物研究开辟了道路。
The molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using non-polyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. Twenty genes, some of which not previously implicated in BPD, were differentially expressed (DE). PCR validation and replication confirmed the implication of these DE genes. Functional in silico analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, an overall increased number of alternative splicing events in BPD was detected, as well as an increase in the number of genes carrying alternative splicing events. Finally, a large reservoir of circRNAs populating brain tissue not affected by BPD is described, while in BPD altered levels of two circular transcripts, cNEBL and cEPHA3, are reported. cEPHA3, hitherto unlinked to BPD, is implicated in developmental processes in the central nervous system. Although we did not perform replication analyses of non-coding RNA findings, our findings hint that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research.