RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression.
RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression.
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DOI：
10.1371/journal.pone.0143563
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Myers RH
中科院分区：
文献类型：
--
作者：
Labadorf A;Hoss AG;Lagomarsino V;Latourelle JC;Hadzi TC;Bregu J;MacDonald ME;Gusella JF;Chen JF;Akbarian S;Weng Z;Myers RH
亨廷顿病（HD）是由亨廷顿（HTT）基因中CAG三核苷酸重复扩增引起的破坏性神经退行性疾病。人类HD大脑中的转录失调已被记录，但尚未完全理解。在这里，我们提出了一个全基因组分析的mRNA表达在人类前额叶皮层从20 HD和49神经病理正常对照使用下一代高通量测序。令人惊讶的是，在28，087个可靠检测到的基因中，19%（5，480）是差异表达的（FDR <0.05），并且主要是上调的。一种新的无假设的基因富集方法，将大的基因列表解剖成功能和转录相关的组，发现差异表达的基因富集免疫反应，神经炎症和发育基因。观察到所有主要脑细胞类型的标志物，表明HD在所研究的脑区域引起全身反应。出乎意料的是，最强烈的差异表达的基因是同源异型基因集（由Hox和其他同源异型盒基因代表），几乎只在HD中表达，这是一种在HD发病机制中没有广泛牵连的基因谱。HD大脑发育过程中转录变化的意义知之甚少，值得进一步研究。炎症的作用和非神经元参与HD发病机制的重要性表明抗炎治疗可能为治疗HD提供重要的机会。
Huntington’s Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.