NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages
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PROVIDER: PRJNA609157 | ENA |
REPOSITORIES: ENA
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Project description:The epigenome defines the cell type, but also possesses plasticity to tune gene expression in the context of extracellular cues. This tuning is evident in immune sentinel cells such as macrophages, which respond to pathogens and cytokines with phenotypic shifts driven by epigenomic reprogramming. Recent studies indicate that this reprogramming arises from the activity of transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB binds not only to available enhancers but may also produce de novo enhancers in previously silent areas of the genome. Here, we show that NFκB reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NFκB activity. In response to different stimuli, NFκB enters the nucleus with variable speed, amplitude, and duration, and may oscillate between the nucleus and cytoplasm. These dynamical features combine to specify the identity and dose of a given stimulus. We demonstrate through live cell imaging, mathematical modeling, and genetic perturbations that NFκB promotes open chromatin and formation of de novo enhancers most strongly when its dynamics are non-oscillatory. These de novo enhancers result in the activation of additional response genes. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.
2021-01-01 | GSE146068 | GEO
Project description: Not available
| S-EPMC8489855 | biostudies-literature
Project description:Macrophages initiate inflammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NFκB activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workflow identified six dynamical features—termed signaling codons—that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjögren’s syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NFκB signaling codons. Thus, the dynamics of NFκB signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inflammatory diseases.
2021-02-18 | GSE162992 | GEO
Project description:Learning the cis sequence elements that determine AP-1 monomer specificity
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Project description:TNF is a key inflammatory cytokine that warns recipient cells of a nearby infection or tissue damage. Acute exposure to TNF activates characteristic oscillatory dynamics of the transcription factor NFκB and induces a characteristic gene expression program; these are distinct from the responses of cells directly exposed to pathogen-associated molecular patterns (PAMPs). Here we report that tonic TNF exposure is critical for safeguarding TNF’s specific functions. In the absence of tonic TNF conditioning, acute exposure to TNF causes 1) NFκB signaling dynamics that are less oscillatory and more like PAMP-responsive NFκB dynamics, 2) immune gene expression that is more similar to the Pam3CSK4-response program, 3) broader epigenomic reprogramming that is characteristic of PAMP-responsive changes. We show that tonic TNF signaling effects subtle changes to TNF receptor availability and dynamics such that enhanced pathway activity results in non-oscillatory NFκB. Our results reveal tonic TNF signaling as a key tissue determinant of the specific characteristics of cellular responses to acute paracrine TNF exposure, and their distinction from responses to direct exposure to PAMPs.
2022-07-27 | GSE209565 | GEO
Project description:Learning the cis sequence elements that determine AP-1 monomer specificity (ChIP-seq data sets)
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Project description:Learning the cis sequence elements that determine AP-1 monomer specificity (RNA-seq data sets)
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Project description:Gonadotrophin-releasing hormone (GnRH) significantly inhibits proliferation of a proportion of cancer cell lines by activating GnRH receptor-G protein signaling. Therefore, manipulation of GnRH receptor signaling may have an under-utilized role in treating certain breast and ovarian cancers. However, the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined. We used transcriptomic and proteomic profiling approaches to characterize the effects of GnRH receptor activation in sensitive cells (HEK293-GnRHR, SCL60) in in vitro and in vivo settings, compared to unresponsive HEK293. Analyses of gene expression demonstrated a dynamic SCL60 response to the GnRH super-agonist Triptorelin. Early and mid-phase changes (0.5-1.0 h) comprised mainly transcription factors. Later changes (8-24 h) included a GnRH target gene, CGA, and up or down-regulation of transcripts encoding signaling and cell division machinery. Pathway analysis exposed identified altered mitogen-activated protein kinase and cell cycle pathways, consistent with occurrence of G2/M arrest and apoptosis. NFκB pathway gene transcripts were differentially expressed between control and Triptorelin-treated SCL60 cultures. Reverse phase protein and phospho-proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during Triptorelin anti-proliferation. Increased phosphorylated NFκB (p65) occurred in SCL60 in vitro, and p-NFκB and IκBε were higher in treated xenografts than controls after 4 days Triptorelin. NFκB inhibition enhanced the anti-proliferative effect of Triptorelin in SCL60 cultures. This study reveals details of pathways interacting with intense GnRH receptor signaling, identifies potential anti-proliferative target genes and implicates the NFκB survival pathway as a node for enhancing GnRH agonist-induced anti-proliferation. 55 samples: 35 SCL60 (15 Control, 20 Treated), 20 HEK293 (12 Control, 8 Treated). Samples collected after 0, 0.5, 1, 2, 8 or 24h after treatment with Triptorelin (100nM) or vehicle control (20% Propylene Glycol solution). SCL60 cells are HEK293 cells stably transfected with a high level of functional rat GnRHR.
2012-12-21 | E-GEOD-27467 | biostudies-arrayexpress
Project description:Aging changes global transcriptome including protein-coding and noncoding RNAs. Whether aging dependent lncRNAs undergo conserved regulation and function still remain unknown. We report aging dependent lncRNAs carry signature of evolutionary constraint and significantly enriched for targets of transcription factors and RNA binding proteins. Aging dependent lncRNAs is conservatively under NFκB pathway regulation. CRISPR screening for NFκB pathway found that aging dependent lncRNAs also extensively regulate NFκB pathway. The human NFKBMARL-1 is an evolutionary conserved lncRNA that can be traced to 29Mya before human. NFKBMARL-1 is induced during aging, inflammation and senescence through NFκB pathway. Reciprocally, NFKBMARL-1 directly regulates NFKBIZ in cis within same topological associated domain (TAD). NFKBMARL-1 binds to enhancer of NFKBIZ and recruits RELA to the NFKBIZ promoters and participates phase separation. These findings reveal that aging dependent lncRNAs are previously under-appreciated contributors to the evolutionary conservation and regulation of NFκB pathway.
2021-03-08 | GSE167504 | GEO
Project description:Aging changes global transcriptome including protein-coding and noncoding RNAs. Whether aging dependent lncRNAs undergo conserved regulation and function still remain unknown. We report aging dependent lncRNAs carry signature of evolutionary constraint and significantly enriched for targets of transcription factors and RNA binding proteins. Aging dependent lncRNAs is conservatively under NFκB pathway regulation. CRISPR screening for NFκB pathway found that aging dependent lncRNAs also extensively regulate NFκB pathway. The human LINC02085 is an evolutionary conserved lncRNA that can be traced to 29Mya before human. LINC02085 is induced during aging, inflammation and senescence through NFκB pathway. Reciprocally, LINC02085 directly regulates NFKBIZ in cis within same topological associated domain (TAD). LINC02085 binds to enhancer of NFKBIZ and recruits RELA to the NFKBIZ promoters and participates phase separation. These findings reveal that aging dependent lncRNAs are previously under-appreciated contributors to the evolutionary conservation and regulation of NFκB pathway.
2021-03-08 | GSE167510 | GEO