基于chip - seq的NRF1靶基因通路分析提出了其参与神经退行性疾病发病机制的逻辑假设。

Gene regulation and systems biology Pub Date : 2013-11-04 eCollection Date: 2013-01-01 DOI:10.4137/GRSB.S13204
Jun-Ichi Satoh, Natsuki Kawana, Yoji Yamamoto
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引用次数: 116

摘要

核呼吸因子1 (NRF1)是一种转录因子,可激活线粒体生物发生和功能所必需的多种核基因的表达,包括线粒体呼吸复合体亚基、血红素生物合成酶和参与线粒体DNA复制和转录的调节因子。越来越多的证据表明,线粒体功能在与衰老相关的神经退行性疾病的大脑中严重受损。为了鉴定可能与神经退行性疾病发病机制相关的人类NRF1靶基因,我们分析了从DNA元件百科全书(ENCODE)项目中检索的NRF1染色质免疫沉淀和深度测序(ChIP-Seq)数据集。总的来说,我们在SK-N-SH人神经母细胞瘤细胞中鉴定了2470个高度严格的蛋白质编码基因ChIP-Seq峰。它们聚集在近端启动子区域,存在nrf1结合的一致序列。这组基于chip - seq的NRF1靶基因包括已知的NRF1靶基因,如EIF2S1、EIF2S2、CYCS、FMR1、FXR2、E2F6、CD47和TOMM34。通过通路分析,确定了位于与线粒体呼吸功能相关的核心通路中的分子在NRF1靶基因中高度富集。此外,我们发现NRF1靶基因在线粒体外生物过程的调控中发挥关键作用,包括RNA代谢、剪接、细胞周期、DNA损伤修复、蛋白质翻译起始和泛素介导的蛋白质降解。我们确定了一组神经退行性疾病相关基因,如帕金森病的PARK2 (Parkin)、PARK6 (Pink1)、PARK7 (DJ-1)和PAELR (GPR37),以及阿尔茨海默病的PSENEN (Pen2)和MAPT (tau),作为以前未被识别的NRF1靶点。这些结果提出了一个合乎逻辑的假设,即NRF1及其靶点的异常调节可能通过干扰多种线粒体和线粒体外功能而参与人类神经退行性疾病的发病机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases.

Nuclear respiratory factor 1 (NRF1) serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits, heme biosynthetic enzymes, and regulatory factors involved in the replication and transcription of mitochondrial DNA. Increasing evidence indicates that mitochondrial function is severely compromised in the brains of aging-related neurodegenerative diseases. To identify the comprehensive set of human NRF1 target genes potentially relevant to the pathogenesis of neurodegenerative diseases, we analyzed the NRF1 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset retrieved from the Encyclopedia of DNA Elements (ENCODE) project. Overall, we identified 2,470 highly stringent ChIP-Seq peaks on protein-coding genes in SK-N-SH human neuroblastoma cells. They were accumulated in the proximal promoter regions with an existence of the NRF1-binding consensus sequence. The set of ChIP-Seq-based NRF1 target genes included known NRF1 targets such as EIF2S1, EIF2S2, CYCS, FMR1, FXR2, E2F6, CD47, and TOMM34. By pathway analysis, the molecules located in the core pathways related to mitochondrial respiratory function were determined to be highly enriched in NRF1 target genes. Furthermore, we found that NRF1 target genes play a pivotal role in regulation of extra-mitochondrial biological processes, including RNA metabolism, splicing, cell cycle, DNA damage repair, protein translation initiation, and ubiquitin-mediated protein degradation. We identified a panel of neurodegenerative disease-related genes, such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) for Parkinson's disease, as well as PSENEN (Pen2) and MAPT (tau) for Alzheimer's disease, as previously unrecognized NRF1 targets. These results suggest a logical hypothesis that aberrant regulation of NRF1 and its targets might contribute to the pathogenesis of human neurodegenerative diseases via perturbation of diverse mitochondrial and extra-mitochondrial functions.

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