背景:对精神分裂症(SZ)患者大脑的转录组学研究产生了关于疾病病理生理学的大量但在很大程度上不一致的发现。这些不一致可能不仅源于疾病的异质性,但也来自对特定皮质区域和蛋白质编码基因的不平衡关注。与蛋白质编码转录物相比,长基因间非编码RNA(lincRNA)显示出更大的大脑区域和疾病反应特异性,将它们定位为SZ相关改变的前瞻性指标。Further,越来越多的人对这种疾病的系统性特征有了新的认识,需要更系统的筛查,包括多个不同的大脑区域。
目的:我们旨在通过检测35个脑区的转录组来鉴定和解释SZ中lincRNA表达谱的改变。
方法:我们测量了从8个成人大脑样本中解剖的35个大脑区域的转录组,四名SZ患者,和四个健康对照,使用高通量RNA测序。对这些数据的分析产生861个注释的人lincRNA,其通过检测阈值。
结果:在861个检测到的lincRNA中,135在SZ中显示出显著的区域依赖性表达改变(双向方差分析,BH调整的p0.05)和37另外显示HC和SZ个体在至少一个区域中的显着差异表达(posthocTukey检验,p0.05)。对于这37种差异表达的lincRNAs(DELs),88%的差异发生在一组包含轴突丰富的脑区和小脑的脑区中。DEL靶标的功能注释进一步揭示了神经元和突触传递术语和途径的明显富集。
结论:我们的研究强调了系统的大脑转录组分析的实用性,该分析依赖于在多个大脑区域测量的表达谱,并挑出白质区域作为进一步SZ研究的前瞻性目标。
BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (
lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions.
OBJECTIVE: We aimed to identify and interpret alterations of the
lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions.
METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold.
RESULTS: Of the 861 detected
lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways.
CONCLUSIONS: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.