Inferring Genome-Wide Functional Modulatory Network: A Case Study on NF-κB/RelA Transcription Factor
Inferring Genome-Wide Functional Modulatory Network: A Case Study on NF-κB/RelA Transcription Factor
复制标题
推断全基因组功能调节网络：NF-kappa B/RelA 转录因子的案例研究
DOI：
10.1089/cmb.2014.0299
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发表时间：
2015-04-01
影响因子：
1.7
通讯作者：
Kudlicki, Andrzej S.
中科院分区：
文献类型：
--
作者：
Li, Xueling;Zhu, Min;Kudlicki, Andrzej S.
不同的途径如何导致特定转录因子 (TF) 的激活并产生特定的效果尚不完全清楚。我们将上下文特异性转录调控建模为调节网络：由 TF、靶基因和调节器组成的三联体。调节剂通常以靶基因特异性作用模式在转录后水平影响特定转录因子的活性。该作用可分为激活或抑制的增强、减弱或反转。作为一个案例研究，我们从大量的表达谱中推断出 NF-kappa B/RelA 的所有潜在调节。预测的调节剂包括许多以前未报道为与 RelA 物理结合但具有相关功能的蛋白质，例如 RNA 加工、细胞周期、线粒体、泛素依赖性蛋白水解和染色质修饰。来自不同过程的调节剂在不同的途径上发挥特定的普遍作用模式。来自非编码 RNA、RNA 结合蛋白、TF 和激酶的调节剂通过与其分子功能和调节水平一致的特定作用模式调节 NF-kappa B/RelA 活性。上皮间质转化 (EMT) 和烧伤损伤中 NF-κB/RelA 的调节网络具有不同的调节剂，包括参与细胞外基质 (FBN1)、细胞骨架调节 (ACTN1) 和转移相关肺腺癌转录物 1 (MALAT1)、长基因间非蛋白编码 RNA 和 EMT 肿瘤抑制 (FOXP1) 的调节剂，以及 TXNIP，用于烧伤的 GAPDH、PKM2、IFIT5、LDHA、NID1 和 TPP1。
How different pathways lead to the activation of a specific transcription factor (TF) with specific effects is not fully understood. We model context-specific transcriptional regulation as a modulatory network: triplets composed of a TF, target gene, and modulator. Modulators usually affect the activity of a specific TF at the posttranscriptional level in a target gene-specific action mode. This action may be classified as enhancement, attenuation, or inversion of either activation or inhibition. As a case study, we inferred, from a large collection of expression profiles, all potential modulations of NF-kappa B/RelA. The predicted modulators include many proteins previously not reported as physically binding to RelA but with relevant functions, such as RNA processing, cell cycle, mitochondrion, ubiquitin-dependent proteolysis, and chromatin modification. Modulators from different processes exert specific prevalent action modes on distinct pathways. Modulators from noncoding RNA, RNA-binding proteins, TFs, and kinases modulate the NF-kappa B/RelA activity with specific action modes consistent with their molecular functions and modulation level. The modulatory networks of NF-kappa B/RelA in the context epithelial-mesenchymal transition (EMT) and burn injury have different modulators, including those involved in extracellular matrix (FBN1), cytoskeletal regulation (ACTN1), and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long intergenic nonprotein coding RNA, and tumor suppression (FOXP1) for EMT, and TXNIP, GAPDH, PKM2, IFIT5, LDHA, NID1, and TPP1 for burn injury.