PDF(Pubmed)
Abstract：
The NF-κB protein p65/RelA plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA regulates gene transcription and alternative splicing through promoter enrichment and genomic exon occupancy, respectively. The intricate ways in which p65/RelA simultaneously governs these functions across various genes remain to be fully elucidated. In this study, we employed the HTLV-1 Tax oncoprotein, a potent activator of NF-κB, to investigate its influence on the three-dimensional organization of the genome, a key factor in gene regulation. We discovered that Tax restructures the 3D genomic landscape, bringing together genes based on their regulation and splicing patterns. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their respective changes in gene expression and alternative splicing. Through dCas9-mediated approaches, we demonstrated that NFKBIA-RELA interaction is required for alternative splicing regulation and is caused by an intragenic enrichment of p65/RelA on RELA. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the integral role of p65/RelA in coordinated regulation of NF-κB-responsive genes at both transcriptional and splicing levels in the context of the 3D genome.
The NF-κB pathway is essential for coordinating gene expression in response to various stimuli, including viral infections. Most studies have focused on the role of NF-κB in transcriptional regulation. In the present study, the impact of the potent NF-κB activator HTLV-1 Tax oncoprotein on the three-dimensional organization of the genome was investigated. Tax-mediated NF-κB activation was found to restructure the 3D genomic landscape in cells and to bring genes together in multigene complexes that are coordinately regulated either transcriptionally or through alternative splicing by NF-κB. Induced coordinate changes in transcription and alternative splicing included the two master genes of NF-κB pathway NFKBIA and RELA. The findings have significant implications for understanding cell fate determination and disease development associated with HTLV-1 infection, as well as chronic NF-κB activation in various human inflammatory diseases and cancer.
The NF-κB pathway is essential for coordinating gene expression in response to various stimuli, including viral infections. Most studies have focused on the role of NF-κB in transcriptional regulation. In the present study, the impact of the potent NF-κB activator HTLV-1 Tax oncoprotein on the three-dimensional organization of the genome was investigated. Tax-mediated NF-κB activation was found to restructure the 3D genomic landscape in cells and to bring genes together in multigene complexes that are coordinately regulated either transcriptionally or through alternative splicing by NF-κB. Induced coordinate changes in transcription and alternative splicing included the two master genes of NF-κB pathway NFKBIA and RELA. The findings have significant implications for understanding cell fate determination and disease development associated with HTLV-1 infection, as well as chronic NF-κB activation in various human inflammatory diseases and cancer.
摘要：
NF-κB蛋白p65/RelA在响应不同刺激时协调基因表达中起关键作用,包括病毒感染.在染色质水平，p65/RelA通过启动子富集和基因组外显子占据调节基因转录和可变剪接，分别。p65/RelA在各种基因中同时控制这些功能的复杂方式仍有待完全阐明。在这项研究中,我们使用了HTLV-1税癌蛋白，一种有效的NF-κB激活剂，为了研究它对基因组三维组织的影响，基因调控的关键因素。我们发现Tax重组了3D基因组景观，基于基因的调控和剪接模式。值得注意的是,我们发现税收诱导的两个主基因NFKBIA和RELA之间的基因-基因接触与它们各自的基因表达和可变剪接变化有关。通过dCas9介导的方法，我们证明了NFKBIA-RELA相互作用是选择性剪接调节所必需的，并且是由RELA上p65/RelA的基因内富集引起的。我们的发现揭示了HTLV-1Tax的新调节机制，并强调了p65/RelA在3D基因组背景下转录和剪接水平上协调调节NF-κB响应基因的整体作用。
NF-κB通路对于协调响应各种刺激的基因表达至关重要，包括病毒感染.大多数研究集中在NF-κB在转录调控中的作用。在本研究中,研究了有效的NF-κB激活剂HTLV-1Tax癌蛋白对基因组三维组织的影响。发现税收介导的NF-κB激活可以重组细胞中的3D基因组景观，并将基因聚集在多基因复合物中，这些复合物在转录上或通过NF-κB的可变剪接进行协调调节。诱导的转录和可变剪接的坐标变化包括NF-κB通路NFKBIA和RELA的两个主基因。这些发现对于理解细胞命运决定和与HTLV-1感染相关的疾病发展具有重要意义。以及各种人类炎症性疾病和癌症中的慢性NF-κB激活。
NF-κB通路对于协调响应各种刺激的基因表达至关重要，包括病毒感染.大多数研究集中在NF-κB在转录调控中的作用。在本研究中,研究了有效的NF-κB激活剂HTLV-1Tax癌蛋白对基因组三维组织的影响。发现税收介导的NF-κB激活可以重组细胞中的3D基因组景观，并将基因聚集在多基因复合物中，这些复合物在转录上或通过NF-κB的可变剪接进行协调调节。诱导的转录和可变剪接的坐标变化包括NF-κB通路NFKBIA和RELA的两个主基因。这些发现对于理解细胞命运决定和与HTLV-1感染相关的疾病发展具有重要意义。以及各种人类炎症性疾病和癌症中的慢性NF-κB激活。
