Dissecting the Regulatory Strategies of NF-κB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics

Ngo, Kim A.; Kishimoto, Kensei; Davis-Turak, Jeremy; Pimplaskar, Aditya; Zhang, Cheng; Spreafico, Roberto; Chen, Emily Y.; Tam, Amy; Ghosh, Gourisankar; Mitchell, Simon; Hoffmann, Alexander

doi:10.1016/j.celrep.2020.01.108

Cited by 48 publications

(46 citation statements)

References 70 publications

(81 reference statements)

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“…To further dissect the molecular mechanism of RELA FUS -driven ependymoma formation, we examined the implication of RELA target genes in the RELA FUS1 transcription network using publicly available Rela ChIP-seq data in murine embryonic fibroblasts (MEFs) after TNF stimulation [ 37 ]. We found that approximately 22% of RELA FUS1 peaks in mEPN cells overlapped with Rela peaks in MEFs (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the canonical NF-κB consensus motif, termed as κB site (5′-GGGRNWYYCC-3′, R = A or G, N = any base, W = A or T, and Y = C or T) was not present among the top 10 motifs in either RELA FUS1 or RELA FUS1−S486E peaks (Additional file 11 : Table S3A) [ 5 , 24 , 36 ]. In turn, when applying the TF motif analysis to Rela Peaks in MEFs [ 37 ], the NF-κB-like motif (5′-KGGAAADYCCM-3′, K = G or T, D = A or G or T, M = A or C) was identified in only 17.4% of the Rela target genes as the most enriched motif, thus confirming the presence of Rela binding on non-NF-κB consensus sequence (Additional file 4 : Fig. S3B).…”

Section: Resultsmentioning

confidence: 99%

“…The RelA ChIP-seq datasets in murine embryonic fibroblasts after three hours of TNF stimulation were obtained from GSE132540 [ 37 ]. Sequencing reads from ChIP-seq experiments were mapped to the hg19 version of the human genome or mm9 version of the mouse genome with Bowtie (v2.2.9) and parameters–local, respectively [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

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C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation

Ozawa¹,

Kaneko²,

Szulzewsky

et al. 2021

acta neuropathol commun

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Recurrent C11orf95-RELA fusions (RELAFUS) are the hallmark of supratentorial ependymomas. The presence of RELA as the fusion partner indicates a close association of aberrant NF-κB activity with tumorigenesis. However, the oncogenic role of the C11orf95 has not been determined. Here, we performed ChIP-seq analyses to explore genomic regions bound by RELAFUS and H3K27ac proteins in human 293T and mouse ependymoma cells. We then utilized published RNA-Seq data from human and mouse RELAFUS tumors and identified target genes that were directly regulated by RELAFUS in these tumors. Subsequent transcription factor motif analyses of RELAFUS target genes detected a unique GC-rich motif recognized by the C11orf95 moiety, that is present in approximately half of RELAFUS target genes. Luciferase assays confirmed that a promoter carrying this motif is sufficient to drive RELAFUS-dependent gene expression. Further, the RELAFUS target genes were found to be overlapped with Rela target genes primarily via non-canonical NF-κB binding sites. Using a series of truncation and substitution mutants of RELAFUS, we also show that the activation domain in the RELAFUS moiety is necessary for the regulation of gene expression of these RELAFUS target genes. Lastly, we performed an anti-cancer drug screening with mouse ependymoma cells and identified potential anti-ependymoma drugs that are related to the oncogenic mechanism of RELAFUS. These findings suggested that RELAFUS might induce ependymoma formation through oncogenic pathways orchestrated by both C11orf95 and RELA target genes. Thus, our study unveils a complex gene function of RELAFUS as an oncogenic transcription factor in RELAFUS positive ependymomas.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation

Ozawa¹,

Kaneko²,

Szulzewsky

et al. 2021

acta neuropathol commun

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“…The SARS-COV-2 virus mainly targets respiratory epithelial cells, alveolar epithelial cells, vascular endothelial cells and pulmonary macrophages, all of which express Angiotensin converting enzyme 2 (ACE2) receptor, triggering the generation of pro- inflammatory cytokines and chemokines (including IL-6, TNF, IL-10 and MCP1) 41 . The NF-kB family member RELA is a widely expressed and effective transcriptional activator that activates the expression of many inflammatory through exposure to pathogens and inflammatory cytokines 42 . RELA may play an important role in the infection of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Investigating the mechanism of ShuFeng JieDu capsule for the treatment of novel Coronavirus pneumonia (COVID-19) based on network pharmacology

Chen¹,

Yin²,

Zhang³

et al. 2020

Int. J. Med. Sci.

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ShuFeng JieDu capsule (SFJDC), a traditional Chinese medicine, has been recommended for the treatment of COVID-19 infections. However, the pharmacological mechanism of SFJDC still remains vague to date. The active ingredients and their target genes of SFJDC were collected from TCMSP. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). NCP-related target genes were collected from GeneCards database. The ingredients-targets network of SFJDC and PPI networks were constructed. The candidate genes were screened by Venn diagram package for enrichment analysis. The gene-pathway network was structured to obtain key target genes. In total, 124 active ingredients, 120 target genes of SFJDC and 251 NCP-related target genes were collected. The functional annotations cluster 1 of 23 candidate genes (CGs) were related to lung and Virus infection. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the key target genes. The results suggested that SFJDC cloud be treated COVID-19 by multi-compounds and multi-pathways, and this study showed that the mechanism of traditional Chinese medicine (TCM) in the treatment of disease from the overall perspective.

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“…Therefore, it is possible that for some cells the promoters of NF-κB-dependent genes are primed in cis to respond rapidly to the increase in NF-κB abundance, for example, through higher accessibility or the pre-loading of poised polymerase. Of note, recent genome-wide analysis of NF-κB-mediated nascent transcription in mouse embryonic fibroblasts revealed a class of very early genes (including TNF ), with nascent transcripts peaking as early as 15 min post stimulation ( Ngo et al., 2020 )—earlier than the peak in NF-κB nuclear concentration. Detailed ChIP analysis at the promoters of these genes might therefore shed light on the nature of first responders.…”

Section: Discussionmentioning

confidence: 99%

First Responders Shape a Prompt and Sharp NF-κB-Mediated Transcriptional Response to TNF-α

et al. 2020

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Summary Nuclear factor (NF)-κB controls the transcriptional response to inflammatory signals by translocating into the nucleus, but we lack a single-cell characterization of the resulting transcription dynamics. Here we show that upon tumor necrosis factor (TNF)-α transcription of NF-κB target genes is heterogeneous in individual cells but results in an average nascent transcription profile that is prompt (i.e., occurs almost immediately) and sharp (i.e., increases and decreases rapidly) compared with NF-κB nuclear localization. Using an NF-κB-controlled MS2 reporter we show that the single-cell nascent transcription is more heterogeneous than NF-κB translocation dynamics, with a fraction of synchronized “first responders” that shape the average transcriptional profile and are more prone to respond to multiple TNF-α stimulations. A mathematical model combining NF-κB-mediated gene activation and a gene refractory state is able to reproduce these features. Our work shows how the expression of target genes induced by transcriptional activators can be heterogeneous across single cells and yet time resolved on average.

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Dissecting the Regulatory Strategies of NF-κB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics

Cited by 48 publications

References 70 publications

C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation

C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation

Investigating the mechanism of ShuFeng JieDu capsule for the treatment of novel Coronavirus pneumonia (COVID-19) based on network pharmacology

First Responders Shape a Prompt and Sharp NF-κB-Mediated Transcriptional Response to TNF-α

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