IκBζ is a dual-use coactivator of NF-κB and POU transcription factors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA998915 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25432840.fastq.gz | Fastqsanger.gz | |||
| SRR25432841.fastq.gz | Fastqsanger.gz | |||
| SRR25432842.fastq.gz | Fastqsanger.gz | |||
| SRR25432843.fastq.gz | Fastqsanger.gz | |||
| SRR25432844.fastq.gz | Fastqsanger.gz |
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Project description:OCA-B, OCA-T1, and OCA-T2 belong to a family of transcriptional coactivators that bind to POU transcription factors (TFs) to regulate gene expression in immune cells. Here, we identify IkBz (encoded by the NFKBIZ gene) as the fourth member of the OCA protein family. While originally discovered as an inducible regulator of NFkB, we show here that IkBz shares a microhomology with OCA proteins and uses this segment to simultaneously bind to POU transcription factors and octamer motif-containing DNA. Our functional reporter assays suggest that IkBz requires its interaction with POU TFs to coactivate immune-related genes. This finding is reinforced by our epigenomic analysis of MYD88 L265P-mutant lymphoma cells, which revealed colocalization of IkBz, the POU transcription factor OCT2, and NFkB:p50 at hundreds of DNA elements harboring octamer and kB motifs. These results suggest that IkBz is a transcriptional coactivator that integrates and amplifies the output of NFkB and POU transcription factors at inducible genes in immune cells.
2024-01-09 | GSE239374 | GEO
Project description:OCA-B, OCA-T1, and OCA-T2 belong to a family of coactivators that bind to POU transcription factors (TFs) to regulate gene expression in immune cells. Here, we identify IκBζ (encoded by the NFKBIZ gene) as an additional coactivator of POU TFs. Although originally discovered as an inducible regulator of NF-κB, we show here that IκBζ shares a microhomology with OCA proteins and uses this segment to bind to POU TFs and octamer-motif-containing DNA. Our functional experiments suggest that IκBζ requires its interaction with POU TFs to coactivate immune-related genes. This finding is reinforced by epigenomic analysis of MYD88L265P-mutant lymphoma cells, which revealed colocalization of IκBζ with the POU TF OCT2 and NF-κB:p50 at hundreds of DNA elements harboring octamer and κB motifs. These results suggest that IκBζ is a transcriptional coactivator that can amplify and integrate the output of NF-κB and POU TFs at inducible genes in immune cells.
| S-EPMC10960667 | biostudies-literature
Project description:Monocyte chemoattractant protein 1 (MCP-1/CCL2) is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive MCP-1 secretion has been linked to many (auto)inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that the atypical inhibitor of NF-κB ζ (IκBζ), a transcriptional co-activator required for the selective expression of a subset of NF-κB target genes, is a key activator of the Ccl2 gene. IκBζ-deficient macrophages exhibited impaired secretion of MCP-1 when challenged with diverse inflammatory stimuli, such as lipopolysaccharide or peptidoglycan. These findings were reflected at the level of Ccl2 gene expression, which was tightly coupled to the presence of IκBζ. Moreover, mechanistic insights acquired by chromatin immunoprecipitation demonstrate that IκBζ is directly recruited to the proximal promoter region of the Ccl2 gene and required for histone H3K9 trimethylation. Finally, IκBζ-deficient mice showed significantly impaired MCP-1 secretion and monocyte infiltration in an experimental model of peritonitis. Together, these findings suggest a distinguished role of IκBζ in mediating the targeted recruitment of monocytes in response to local inflammatory events. Peritoneal macrophages from Wildtype and IκBζ-Knockout mice were either stimulated with 1µg/ml LPS for 4h or left untreated (triplicates each)
2013-04-09 | E-GEOD-43075 | biostudies-arrayexpress
Project description:Background: IκBζ, a rather unknown co-regulator of NF-κB, is mostly inducibly expressed and can either activate or repress a specific subset of NF-κB target genes. While its role as a transcriptional regulator of various cytokines and chemokines in immune cells has been revealed, IκBζ’s function in solid cancer remains unclear. Methods: We investigated IκBζ expression in melanoma, and assessed its impact on target gene expression, tumor growth, and response to immunotherapy in melanoma cell lines, mouse models, and patient samples. Results: Unlike in other cell types, IκBζ protein was found to be constitutively expressed in a subfraction of melanoma cell lines, and around 35% of melanoma cases. This atypical expression pattern of IκBζ did not correlate with its mRNA levels or known driver mutations, but instead seemed to result from changes in its post-transcriptional or post-translational regulation. Deleting constitutively expressed IκBζ abrogated the activity and chromatin association of STAT3 and p65, leading to reduced expression of the pro-proliferative cytokines IL-1β and IL-6 in melanoma cells. Consequently, loss of tumor-derived IκBζ suppressed self-sustained melanoma cell growth both in vitro and in vivo. Additionally, constitutive IκBζ expression suppressed the induction of the chemokines CXCL9, CXCL10, and CCL5, which impaired the recruitment of NK and CD8+ T-cells to the tumor, causing resistance to α-PD-1 immunotherapy in mice. Furthermore, the expression of tumor-derived IκBζ also correlated with the absence of CD8+ T-cells in human melanoma samples and progressive disease during immunotherapy. Conclusion: We propose that tumor-derived IκBζ could serve as a new therapeutic target and prognostic marker that characterizes melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses. Targeting IκBζ expression might open up a new therapy option to re-establish the recruitment of cytotoxic cells, thereby resensitizing for immunotherapy.
2025-04-29 | GSE277888 | GEO
Project description:Background: IκBζ, a rather unknown co-regulator of NF-κB, is mostly inducibly expressed and can either activate or repress a specific subset of NF-κB target genes. While its role as a transcriptional regulator of various cytokines and chemokines in immune cells has been revealed, IκBζ’s function in solid cancer remains unclear. Methods: We investigated IκBζ expression in melanoma, and assessed its impact on target gene expression, tumor growth, and response to immunotherapy in melanoma cell lines, mouse models, and patient samples. Results: Unlike in other cell types, IκBζ protein was found to be constitutively expressed in a subfraction of melanoma cell lines, and around 35% of melanoma cases. This atypical expression pattern of IκBζ did not correlate with its mRNA levels or known driver mutations, but instead seemed to result from changes in its post-transcriptional or post-translational regulation. Deleting constitutively expressed IκBζ abrogated the activity and chromatin association of STAT3 and p65, leading to reduced expression of the pro-proliferative cytokines IL-1β and IL-6 in melanoma cells. Consequently, loss of tumor-derived IκBζ suppressed self-sustained melanoma cell growth both in vitro and in vivo. Additionally, constitutive IκBζ expression suppressed the induction of the chemokines CXCL9, CXCL10, and CCL5, which impaired the recruitment of NK and CD8+ T-cells to the tumor, causing resistance to α-PD-1 immunotherapy in mice. Furthermore, the expression of tumor-derived IκBζ also correlated with the absence of CD8+ T-cells in human melanoma samples and progressive disease during immunotherapy. Conclusion: We propose that tumor-derived IκBζ could serve as a new therapeutic target and prognostic marker that characterizes melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses. Targeting IκBζ expression might open up a new therapy option to re-establish the recruitment of cytotoxic cells, thereby resensitizing for immunotherapy.
2025-04-29 | GSE277887 | GEO
Project description:Monocyte chemoattractant protein 1 (MCP-1/CCL2) is critically involved in directing the migration of blood monocytes to sites of inflammation. Consequently, excessive MCP-1 secretion has been linked to many (auto)inflammatory diseases, whereas a lack of expression severely impairs immune responsiveness. We demonstrate that the atypical inhibitor of NF-κB ζ (IκBζ), a transcriptional co-activator required for the selective expression of a subset of NF-κB target genes, is a key activator of the Ccl2 gene. IκBζ-deficient macrophages exhibited impaired secretion of MCP-1 when challenged with diverse inflammatory stimuli, such as lipopolysaccharide or peptidoglycan. These findings were reflected at the level of Ccl2 gene expression, which was tightly coupled to the presence of IκBζ. Moreover, mechanistic insights acquired by chromatin immunoprecipitation demonstrate that IκBζ is directly recruited to the proximal promoter region of the Ccl2 gene and required for histone H3K9 trimethylation. Finally, IκBζ-deficient mice showed significantly impaired MCP-1 secretion and monocyte infiltration in an experimental model of peritonitis. Together, these findings suggest a distinguished role of IκBζ in mediating the targeted recruitment of monocytes in response to local inflammatory events.
2013-04-09 | GSE43075 | GEO
Project description:Skin microbiota affect systemic inflammation through mechanisms that have not been completely elucidated. We previously demonstrated that keratinocyte-specific IκBζ-deficient mice spontaneously develop autoimmune inflammation resembling human Sjögren syndrome. In this study, we examined how IκBζ-deficient epidermis dictates systemic autoimmune inflammation onset. To examine if IκBζ-deficient keratinocytes are susceptible to apoptotic stimuli in a steady state, we performed microarray analysis of untreated murine back epidermis. Data indicate that IκBζ-deficient epidermis is susceptible to environment antigens through apoptosis-related gene upregulation
2022-08-11 | GSE165515 | GEO
Project description:Non-consensus binding sites of transcription factors are often observed within the promoters and enhancers of various genes; however, their effect on transcriptional strength is unclear. Within the promoters and enhancers of NF-κB-responsive genes, we identified clusters of non- consensus κB DNA sites, many exhibiting low affinity for NF-κB in vitro. Deletion of these sites demonstrated their collective critical role in transcription. We explored how these “weak” κB sites exert their influence, especially given the typically low nuclear concentration of NF-κB. Using proteomics approaches, we identified additional nuclear factors, including other DNA-binding TFs, that could interact with κB site-bound NF-κB RelA without their direct interaction to DNA. ChIP- seq and RNA-seq analyses suggest that these accessory TFs, referred to as the TF-cofactors of NF-κB, facilitate dynamic recruitment of NF-κB to the clustered κB sites. Overall, the occupancy of NF-κB at promoters and enhancers appears to be defined by a collective contribution from all κB sites, both weak and strong, in association with specific cofactors. This congregation of multiple factors within dynamic transcriptional complexes is likely a common feature of transcriptional programs.
2025-10-13 | PXD065004 | Pride
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) fibroblasts and induced pluripotent stem cells (iPSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS fibroblasts were reprogrammed. RNA was extracted and transcriptional profiling was obtained with GeneChip Human Exon 1.0 ST Arrays.
2015-07-01 | E-GEOD-65170 | biostudies-arrayexpress
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) mesenchymal stem cells (MSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS MSCs were differentiated into bone in the presence or absence of sodium salicylate. Total RNA was extracted and global gene expression was analyzed.
2015-07-01 | E-GEOD-65172 | biostudies-arrayexpress