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Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation

ABSTRACT: The p65/RelA factor of NF-κB plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA governs gene transcription and alternative splicing (AS) through promoter enrichment and genomic exon occupancy, respectively. However, the mechanisms underlying the coordination of these processes remain elusive. In this study, we employed the HTLV-1 Tax viral oncoprotein, a potent activator of NF-κB, to investigate the integrative relationship between 3D chromatin architecture and NF-κB-regulated AS. Our analysis revealed that Tax induces a significant reorganization of the 3D genome, resulting in the formation of multigene complexes that comprise genes co-regulated in transcription and in AS. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their differential regulation in gene expression and alternative splicing, respectively. 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. Via this mechanism, Tax promotes the expression of the splice isoform RELAE6 that exhibits specific gene transactivation capacity at the protein level. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the crucial role of p65/RelA in coordinated regulation of NF-κB-responsive genes at both transcriptional and alternative splicing levels in the context of the 3D genome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233888 | GEO | 2024/02/03

REPOSITORIES: GEO

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Gene-to-gene coordinated regulation of transcription and alternative splicing by 3D chromatin remodeling upon NF-κB activation

Project description:The p65/RelA factor of NF-κB plays a pivotal role in coordinating gene expression in response to diverse stimuli, including viral infections. At the chromatin level, p65/RelA governs gene transcription and alternative splicing (AS) through promoter enrichment and genomic exon occupancy, respectively. However, the mechanisms underlying the coordination of these processes remain elusive. In this study, we employed the HTLV-1 Tax viral oncoprotein, a potent activator of NF-κB, to investigate the integrative relationship between 3D chromatin architecture and NF-κB-regulated AS. Our analysis revealed that Tax induces a significant reorganization of the 3D genome, resulting in the formation of multigene complexes that comprise genes co-regulated in transcription and in AS. Notably, we found that the Tax-induced gene-gene contact between the two master genes NFKBIA and RELA is associated with their differential regulation in gene expression and alternative splicing, respectively. 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. Via this mechanism, Tax promotes the expression of the splice isoform RELAE6 that exhibits specific gene transactivation capacity at the protein level. Our findings shed light on new regulatory mechanisms upon HTLV-1 Tax and underscore the crucial role of p65/RelA in coordinated regulation of NF-κB-responsive genes at both transcriptional and alternative splicing levels in the context of the 3D genome.

2024-02-03 | GSE233887 | GEO

Intragenic recruitment of NF-kB drives splicing modifications upon activation by the oncogene Tax of HTLV-1

Project description:Chronic NF-kB activation in inflammation and cancer has long been linked to persistent activation of NF-kB–responsive gene promoters. However, NF-kB factors also massively bind to gene bodies. Here, we demonstrate that recruitment of the NF-kB factor RELA to intragenic regions regulates alternative splicing upon NF-kB activation by the viral oncogene Tax of HTLV-1. Integrative analyses of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17, in an NF-kB activation–dependent manner. This leads to alternative splicing of target exons due to the RNA helicase activity of DDX17. Similar results were obtained upon Tax-independent NF-kB activation, indicating that Tax likely exacerbates a physiological process where RELA provides splice target specificity. Collectively, our results demonstrate a physical and direct involvement of NF-kB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-kB–related diseases.

2020-05-12 | GSE123752 | GEO

A single Thr505 phospho-site mutation reveals an important role for the RelA NF-κB subunit in liver regeneration and cancer

Project description:Post-translational modification of NF-κB subunits provides a mechanism to differentially regulate their activity in response to the many stimuli that can induce this pathway. However, the physiological significance of these modifications is largely unknown and it remains unclear if these have a critical role in the normal and pathological functions of NF-κB in vivo. Among these, phosphorylation of the RelA(p65) Thr505 residue has been described as an important regulator of NF-κB activity in cell lines but its physiological significance was not known. Therefore, to learn more about the role of this pathway in vivo, we generated a knockin mouse with a RelA T505A mutation. Unlike RelA knockout mice, the RelA T505A mice develop normally but exhibit aberrant hepatocyte proliferation following liver partial hepatectomy or damage resulting from carbon tetrachloride treatment. Consistent with these effects, RelA T505A mice exhibit earlier onset of cancer in the N-nitrosodiethylamine (DEN) model of hepatocellular carcinoma. This data reveals a critical pathway controlling NF-κB function in the liver that acts to suppress tumour-promoting activities of RelA.

2015-11-30 | E-MTAB-3596 | biostudies-arrayexpress

Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function.

Project description:Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment results in gene expression changes in lineage-Flk2-c-kit+Sca-1+ cells from mouse bone marrow. We analyzed lineage-Flk2-c-kit+Sca-1+ cells from the bone marrow of p65 wild-type or knockout mice using the Affymetrix Mouse Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. No technical replicates were performed.

2013-04-04 | E-GEOD-45755 | biostudies-arrayexpress

Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function.

Project description:Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment results in gene expression changes in lineage-Flk2-c-kit+Sca-1+ cells from mouse bone marrow.

2013-04-04 | GSE45755 | GEO

RelA and RelB-dependent transcriptome analysis in lymphotoxin-ß receptor stimulated mouse embryonic fibroblasts

Project description:Background: Lymphotoxin signaling via the lymphotoxin-β receptor (LTβR) has been implicated in several biological processes, ranging from development of secondary lymphoid organs, maintenance of splenic tissue, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTβR crosslinking is NF-κB. Two signaling pathways have been described that result in the activation of classical p50-RelA and alternative p52-RelB NF-κB heterodimers. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LTβR in mouse embryoni fibroblasts (MEF) and its regulation by the RelA and RelB subunits of NF-κB. We describe novel LTβR-responsive genes that are regulated by RelA and/or RelB. Interestingly, we found that the majority of LTβR-regulated genes require the presence of both RelA and RelB, suggesting significant crosstalk between the two NF-κB activation pathways. Gene Ontology (GO) analysis confirmed that LTβR-NF-κB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTβR signaling. Moreover, we show that activation of the LTβR inhibits the expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-γ (pparg), suggesting that LTβR signaling may interfere with adipogenic differentiation. Conclusions: Thus, microarray analysis of LTβR-stimulated fibroblasts revealed further insight into the transcriptional response of LTβR signaling and its regulation by the NF-κB family members RelA and RelB. Keywords: cell type comparison (wt vs relA-/- vs relB-/-) after genetic modification using a time course for each cell type (wt, relA-/-, relB-/-) two time points were analysed (0h as control and 10h) using 3 technical replicates resulting in 18 samples in total

2008-12-17 | E-GEOD-11963 | biostudies-arrayexpress

RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation [ChIP-Seq]

Project description:Cellular response to ionizing radiation involves activation of the p53-dependent pathways and activation of the atypical NF-κB pathway. Mechanisms of the crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Novel genes potentially (co)regulated by p53 and NF-κB were found using high-throughput genomics screening in human osteosarcoma U2-OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-κB subunit) genes was analyzed by RNA-Seq while radiation-induced binding of p53 and RelA (p65) in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR. A subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA were identified. Competition for the same transcriptional coactivators of p53 and NF-κB was the most probable mechanism of a frequent antagonistic effect of the TP53 and RELA silencing. However, this mode of regulation was noted for 3 genes where radiation-induced binding of both p53 and RelA was observed, namely IL4I1, SERPINE1, and CDKN1A. This suggested a possibility of a direct antagonistic (co)regulation by both factors: activation by NF-κB and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-κB of CDKN1A and SERPINE1. On the other hand, radiation-induced binding of both p53 and RelA was observed in a putative regulatory region of RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors.

2018-02-19 | GSE110800 | GEO

Highly selective HSP90 inhibitor, pimitespib, demonstrates its potent growth suppressive activity to adult T-cell leukemia in preclinical models (Pt1-3).

Project description:Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy.

2022-02-18 | GSE168557 | GEO

Highly selective HSP90 inhibitor, pimitespib, demonstrates its potent growth suppressive activity to adult T-cell leukemia in preclinical models (Su9T01).

2022-02-18 | GSE168558 | GEO

Highly selective HSP90 inhibitor, pimitespib, demonstrates its potent growth suppressive activity to adult T-cell leukemia in preclinical models (OATL4).

2022-02-18 | GSE168556 | GEO