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首页> 外文期刊>Epigenetics & Chromatin >HOXA repression is mediated by nucleoporin Nup93 assisted by its interactors Nup188 and Nup205
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HOXA repression is mediated by nucleoporin Nup93 assisted by its interactors Nup188 and Nup205

机译：HOXA抑制是由核孔蛋白Nup93介导，其相互作用因子Nup188和Nup205辅助

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Background The nuclear pore complex (NPC) mediates nuclear transport of RNA and proteins into and out of the nucleus. Certain nucleoporins have additional functions in chromatin organization and transcription regulation. Nup93 is a scaffold nucleoporin at the nuclear pore complex which is associated with human chromosomes 5, 7 and 16 and with the promoters of the HOXA gene as revealed by ChIP-on-chip studies using tiling microarrays for these chromosomes. However, the functional consequences of the association of Nup93 with HOXA is unknown. Results Here, we examined the association of Nup93 with the HOXA gene cluster and its consequences on HOXA gene expression in diploid colorectal cancer cells (DLD1). Nup93 showed a specific enrichment ~1?Kb upstream of the transcription start site of each of the HOXA1, HOXA3 and HOXA5 promoters, respectively. Furthermore, the association of Nup93 with HOXA was assisted by its interacting partners Nup188 and Nup205. The depletion of the Nup93 sub-complex significantly upregulated HOXA gene expression levels. However, expression levels of a control gene locus (GLCCI1) on human chromosome 7 were unaffected. Three-dimensional fluorescence in situ hybridization (3D-FISH) analyses revealed that the depletion of the Nup93 sub-complex (but not Nup98) disengages the HOXA gene locus from the nuclear periphery, suggesting a potential role for Nup93 in tethering and repressing the HOXA gene cluster. Consistently, Nup93 knockdown increased active histone marks (H3K9ac), decreased repressive histone marks (H3K27me3) on the HOXA1 promoter and increased transcription elongation marks (H3K36me3) within the HOXA1 gene. Moreover, the combined depletion of Nup93 and CTCF (a known organizer of HOXA gene cluster) but not Nup93 alone, significantly increased GLCCI1 gene expression levels. Taken together, this suggests a novel role for Nup93 and its interactors in repressing the HOXA gene cluster. Conclusions This study reveals that the nucleoporin Nup93 assisted by its interactors Nup188 and Nup205 mediates the repression of HOXA gene expression.
机译：背景技术核孔复合物（NPC）介导RNA和蛋白质向核内和向核外的核转运。某些核孔蛋白在染色质组织和转录调控中具有其他功能。 Nup93是位于核孔复合体上的支架核孔蛋白，与人染色体5、7和16以及HOXA基因的启动子有关，这是通过芯片上芯片研究（使用这些染色体的平铺微阵列）揭示的。但是，Nup93与HOXA关联的功能后果尚不清楚。结果在这里，我们检查了Nup93与HOXA基因簇的关联及其对二倍体结直肠癌细胞（DLD1）HOXA基因表达的影响。 Nup93在HOXA1，HOXA3和HOXA5启动子的转录起始位点上游分别显示了〜1？Kb的特异性富集。此外，Nup93与HOXA的关联得到了其交互伙伴Nup188和Nup205的协助。 Nup93亚复合物的耗竭显着上调了HOXA基因表达水平。但是，人类染色体7上的控制基因位点（GLCCI1）的表达水平不受影响。三维荧光原位杂交（3D-FISH）分析显示，Nup93亚复合物（但不是Nup98）的耗竭使HOXA基因位点与核外围脱离，这表明Nup93在束缚和抑制HOXA中的潜在作用基因簇。一致地，Nup93敲低会增加HOXA1启动子上的活性组蛋白标记（H3K9ac），抑制性组蛋白标记（H3K27me3）和增加的转录延伸标记（H3K36me3）。此外，Nup93和CTCF（HOXA基因簇的已知组织者）（而不是单独的Nup93）的联合消耗显着增加了GLCCI1基因表达水平。两者合计，这表明Nup93及其相互作用因子在抑制HOXA基因簇中具有新作用。结论这项研究揭示了核孔蛋白Nup93在其相互作用因子Nup188和Nup205的辅助下介导了HOXA基因表达的抑制。

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