LncRNA CARINH regulates expression and function of innate transcription factor IRF1 in macrophages [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1039021 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26786734_1.fastq.gz | Fastqsanger.gz | |||
| SRR26786734_2.fastq.gz | Fastqsanger.gz | |||
| SRR26786735_1.fastq.gz | Fastqsanger.gz | |||
| SRR26786735_2.fastq.gz | Fastqsanger.gz | |||
| SRR26786736_1.fastq.gz | Fastqsanger.gz |
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Project description:LncRNA CARINH regulates expression and function of innate transcription factor IRF1 in macrophages [RNA-Seq 2]
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Project description:Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Endotoxin exposure causes widespread nucleosome remodeling and formation of thousands of de novo enhancers. However, it remains unclear how signal-dependent transcription factors collaborate to remodel the epigenome. Here, we dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) catalyzes the opening of chromatin and the formation of de novo enhancers. We found that endotoxin-activated IRF3 is directly responsible for the induction of few de novo enhancers but is broadly required indirectly through activation of type I interferon-induced ISGF3. However, ISGF3 has limited capacity to initiate enhancer formation by itself – it must cooperate with IRF1, particularly at locations where the chromatin is less accessible. At these locations, IRF1 is required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because IRF1 expression must be induced by NFκB, IRF-regulated enhancers require that both branches of the innate immune signaling network, IRF3 and NFκB, are activated. However, type II interferon, typically produced by T-cells, may also induce IRF1 via the STAT1 homodimer GAF. We show that in this context, IRF1 is also responsible for opening inaccessible chromatin sites that can then be exploited by GAF to form de novo enhancers. Our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogen or IFNγ-secreting T cells, but not bystander macrophages exposed only to transient type I interferon.
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Project description:Analysis of bone-marrow derived macrophages (BMDMs) stimulated with single or combinatorial TLR agonist and MEK1/2 inhibitor in wild-type and Irf1-/- macrophages. Results provide insights into the versatile but yet uncharacterized roles of IRF1 in TLR-MEK1/2-ERK MAPK signaling.
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Project description:Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for the activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell. We used microarrays to explore the gene expression profiles differentially expressed in Francisella-infected bone marrow-derived macrophages (BMDMs) isolated from Irf1-/-, Ifnar1-/-, Aim2-/- and wild-type mice.
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Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.
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Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.
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Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.
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