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首页> 外文期刊>Biochimica et Biophysica Acta. Gene Regulatory Mechanisms >Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells
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Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells

机译:与转录组的STAT3结合和表观遗传修饰测绘的基因组的整合揭示了胶质瘤细胞中的新型STAT3靶基因

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Background: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown.Results: We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells.Conclusions: Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.
机译:背景:转录3(STAT3)的信号传感器和活化剂在许多人类肿瘤中组成型,包括胶质瘤,并调节含有增殖,存活,凋亡,血管生成和免疫调节的基因的表达。已被证明只有一小部分这些基因是直接的STAT3目标。在Gliomas,STAT3可以根据靶基因的肿瘤遗传背景在很大程度上发挥肿瘤抑制或致癌作用。结果:我们使用染色质免疫沉淀,启动子​​微阵列和深度测序来评估磷酸的基因组(P)-Stat3 H3K4ME3和H3AC在C6胶质瘤细胞中的表观遗传修饰。该组合评估鉴定了1200个基因的列表,其启动子具有STAT3结合位点和表观遗传标记的具有活性转录基因的特征。在抑制JAK2 / Stat3信号传导后,STAT3和组蛋白标记数据也与来自C6胶质瘤细胞的一组微阵列数据相交。随后,我们发现由P-Stat3占用的284个基因,激活组蛋白标记和转录变化。筛选新的基因筛选其潜在的血管生成的潜在参与,并且在人胶质瘤细胞中通过Chip-PCR和Stat3敲低验证最有趣的命中。结论:无声基因,组蛋白标记和P-STAT3在附近转录时的无随机关联。观察到遗址,符合其在具有特定遗传背景的胶质瘤细胞中靶基因转录调节中的抑制作用。

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