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首页> 外文期刊>BMC Genomics >ITGA6 gene silencing by RNA interference modulates the expression of a large number of cell migration-related genes in human thymic epithelial cells
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ITGA6 gene silencing by RNA interference modulates the expression of a large number of cell migration-related genes in human thymic epithelial cells

机译：RNA干扰ITGA6基因沉默调节人胸腺上皮细胞中大量细胞迁移相关基因的表达

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BackgroundThe thymic epithelium is the major microenvironmental component of the thymus, the primary lymphoid organ responsible for the generation of T lymphocytes. Thymic epithelial cells (TEC) control intrathymic T cell differentiation by means of distinct types of interactions. TEC constitutively produce chemokines and extracellular matrix ligands (such as laminin and fibronectin) and express corresponding receptors, which allow thymocytes to migrate in a very ordered fashion. We previously showed that laminin mediates TEC/thymocyte interactions in both mice and humans. More recently, we used RNAi technology to knock-down the ITGA5 gene (which encodes CD49e, the integrin α-chain subunit of the fibronectin receptor VLA-5) in cultured human TEC. Using a similar strategy, herein we knocked-down the ITGA6 gene, which encodes CD49f, the α-chain of two integrin-type laminin receptors, namely VLA-6 (α6β1) and α6β4.ResultsWe first confirmed that RNAi-induced knock-down of the ITGA6 gene was successful, at both transcription and translational levels, with a significant decrease in the membrane expression of CD49f, apart from CD49b, CD49c and CD49d, ascertained by cytofluorometry on living TEC. We also demonstrated that such knock-down promotes a decrease in cell adhesion to laminin. Using quantitative PCR, we demonstrated that gene expression of other integrin α-chains were concomitantly down-regulated, particularly those which form other laminin receptors, including ITGA1, ITGA2 and ITGA7. Interestingly enough, LAMA1 gene expression (whose corresponding protein chain is part of laminin-111) was largely increased in ITGA6 knocked-down TEC cultures. Lastly, the network complexity of gene expression under ITGA6 influence is much broader, since we found that other cell migration-related genes, namely those coding for various chemokines, are also modulated when IGTA6 is knocked-down.ConclusionThe data presented herein clearly show that down regulation of ITGA6 gene in the human thymic epithelium triggers a complex cascade of effects upon the expression levels of several other cell migration-related genes, including extracellular matrix and chemokine ligands and receptors. Taken together, these data unravel the concept that the expression of genes involved in controlling of thymocyte migration by the thymic microenvironment should be regarded as complex networks, so that a defect in the expression of one single gene may reflect in an amplified cascade with functional consequences for TEC adhesion onto the natural ligand and potential consequences upon the normal patterns of TEC/thymocyte interactions.
机译：背景胸腺上皮是胸腺的主要微环境成分，胸腺是负责T淋巴细胞生成的主要淋巴器官。胸腺上皮细胞（TEC）通过不同类型的相互作用控制胸腺内T细胞分化。 TEC组成型产生趋化因子和细胞外基质配体（如层粘连蛋白和纤连蛋白）并表达相应的受体，从而使胸腺细胞以非常有序的方式迁移。我们以前显示层粘连蛋白介导小鼠和人类中TEC /胸腺细胞的相互作用。最近，我们使用RNAi技术敲除培养的人TEC中的ITGA5基因（编码CD49e，纤连蛋白受体VLA-5的整合素α链亚基）。我们使用类似的策略敲除ITGA6基因，该基因编码CD49f，这是两个整合素型层粘连蛋白受体VLA-6（α6β1）和α6β4的α链。结果我们首先证实了RNAi诱导的敲除。 ITGA6基因的成功表达，无论在转录水平还是翻译水平，除CD49b，CD49c和CD49d以外，CD49f的膜表达均显着下降，这是通过活体TEC上的细胞荧光法确定的。我们还证明了这种敲低会促进细胞对层粘连蛋白的粘附性降低。使用定量PCR，我们证明了其他整联蛋白α链的基因表达也随之下调，特别是那些形成其他层粘连蛋白受体的基因，包括ITGA1，ITGA2和ITGA7。有趣的是，在ITGA6敲除的TEC培养物中，LAMA1基因表达（其相应的蛋白链是laminin-111的一部分）大大增加了。最后，ITGA6影响下基因表达的网络复杂性要广得多，因为我们发现敲除IGTA6时还调节了其他与细胞迁移相关的基因，即编码各种趋化因子的基因。结论本文提供的数据清楚地表明：人胸腺上皮中ITGA6基因的下调触发了对其他几种细胞迁移相关基因（包括细胞外基质，趋化因子配体和受体）表达水平的复杂级联作用。综上所述，这些数据揭示了一个概念，即涉及通过胸腺微环境控制胸腺细胞迁移的基因的表达应被视为复杂的网络，因此，单个基因表达的缺陷可能反映在放大的级联反应中，从而产生功能性后果。 TEC粘附到天然配体上，以及对TEC /胸腺细胞相互作用正常模式的潜在影响。

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