Geneexpression profile of THP-1 monocytesfollowing knockdown of DAP12, a causativegene for Nasu-Hakola disease.
Geneexpression profile of THP-1 monocytesfollowing knockdown of DAP12, a causativegene for Nasu-Hakola disease.
复制标题
DAP12（Nasu-Hakola 病的致病基因）敲低后 THP-1 单核细胞的基因表达谱。
DOI：
10.1007/s10571-011-9769-z
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Tabunoki H.
中科院分区：
文献类型：
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作者：
Satoh J;Shimamura Y;Tabunoki H.
Nasu-Hakola病（NHD），也被称为多囊性脂膜性骨发育不良伴硬化性白质脑病，是一种罕见的常染色体隐性遗传病，其特征是进行性早老性痴呆和多灶性骨囊肿的形成，由DAP12或TREM2的功能丧失突变引起。TREM2和DAP12构成受体/接头复合物，在破骨细胞、树突状细胞、巨噬细胞、单核细胞和小胶质细胞上表达。目前，NHD中白质脑病和骨囊肿发展的确切分子机制在很大程度上仍然未知。我们建立了稳定表达靶向DAP12的小干扰RNA的THP-1人单核细胞克隆，作为NHD的细胞模型。全基因组转录组分析发现，在DAP12敲低的细胞中，一组22个基因持续下调。它们构成了与细胞间信号传导和相互作用、血液系统发育和功能以及炎症反应所定义的网络密切相关的分子网络，其中NF-κB起着中心调节作用。这些结果表明，人类单核细胞中DAP12的分子缺陷解除了NHD中维持髓细胞功能的关键基因网络的调控。
Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, is a rare autosomal recessive disorder characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor complex expressed on osteoclasts, dendritic cells, macrophages, monocytes, and microglia. At present, the precise molecular mechanisms underlying development of leukoencephalopathy and bone cysts in NHD remain largely unknown. We established THP-1 human monocyte clones that stably express small interfering RNA targeting DAP12 for serving as a cellular model of NHD. Genome-wide transcriptome analysis identified a set of 22 genes consistently downregulated in DAP12 knockdown cells. They constituted the molecular network closely related to the network defined by cell-to-cell signaling and interaction, hematological system development and function, and inflammatory response, where NF-κB acts as a central regulator. These results suggest that a molecular defect of DAP12 in human monocytes deregulates the gene network pivotal for maintenance of myeloid cell function in NHD.