Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.
Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.
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DOI：
10.1007/s00335-015-9568-9
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发表时间：
2015-06
期刊：
影响因子：
2.5
通讯作者：
Bhattacharya, Sujoy
中科院分区：
文献类型：
--
作者：
Chaum, Edward;Winborn, Christina S.;Bhattacharya, Sujoy
肿瘤抑制因子p53是细胞周期停滞、衰老、凋亡和先天免疫重要基因的主要调节因子，并且最近被认为与视网膜老化有关。在这项研究中，我们试图确定的遗传网络，调节p53在视网膜功能的数量性状基因座（QTL）分析。首先，我们检查了从年轻和老年人供体中采集的原代视网膜色素上皮（RPE）细胞中p53、已知p53靶蛋白和先天免疫系统激活标志物的激活和表达水平的年龄相关变化。我们观察到p53、活化的caspase-1、CDKN 1A、CDKN 2A（p16 INK 4a）、TLR 4和IFNα在老化的原代RPE细胞系中的表达增加。我们使用基于QTL系统生物学的方法，使用汉密尔顿眼科研究所（HEI）视网膜数据集（www.genenetwork.org）来鉴定在重组近交BXD小鼠品系中调节p53途径中的基因表达的基因组基因座。我们在1号染色体上（区域172- 177 Mb）鉴定了一个显著的调控Cdkn 1a表达的反式QTL。该QTL基因座中的许多基因参与先天免疫应答，包括Fc受体、干扰素诱导家族基因和CD 12。重要的是，我们发现RPE培养物中FCGR 3A和FMN 2的年龄相关性增加以及IFI 16水平的降低。存在复杂的多基因先天免疫位点，其控制RPE中p53途径中的基因表达，这可能在调节视网膜中与年龄相关的变化中起重要作用。
The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53, known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFNα in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset (www.genenetwork.org) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology based approach. We identified a significant trans-QTL on chromosome 1 (region 172–177Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc-receptors, interferon-inducible family genes and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.
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影响因子：
3.7
作者：
Chen H;Liu B;Lukas TJ;Neufeld AH
通讯作者：
Neufeld AH
影响因子：
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作者：
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影响因子：
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影响因子：
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作者：
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