Histone methylation regulator PTIP orchestrates inflammatory responses via modulating acetylation state of cis-regulatory elements [BMDM-RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE163208 | GEO | 2022/12/30
REPOSITORIES: GEO
Similar Datasets
Project description:Innate immune cells including myeloid cells exhibit dynamic cellular switches during inflammatory and immune responses against infection. These processes are tightly regulated at different levels including the cis-regulatory elements of immune cells. However, it remains unclear how the dynamic states of cis-regulatory elements of innate immune cells are controlled during inflammatory responses. Here we found that histone methylation regulator PTIP orchestrates inflammatory responses of macrophages through regulating acetylation state of enhancers and promoters. Rapid elevated expression of PTIP is observed in primary human and mouse macrophages upon lipopolysaccharide (LPS) stimulation. Loss of PTIP represses transcription of pro-inflammatory genes, and activates expression of anti-inflammatory genes. Mechanistically, we found that, independent of its function in histone methylation, PTIP interacts with acetyltransferase p300 and deacetylase HDACs, and serves as a beacon to recruit them to specific sites of inflammatory genes respectively. PTIP deficiency alters H3K27 acetylation state of cis-regulatory elements of inflammatory genes. Moreover, PTIP and c-JUN shape a positive and feedforward regulatory circuit. In addition, PTIP deletion sustains immunosuppressive function of tumor-associated macrophages (TAMs) and promotes tumor growth. Overall, our findings uncover a critical role of PTIP in altering the acetylation state of cis-regulatory regions and fine-tuning the inflammatory responses of innate immune cells.
2022-12-30 | GSE163221 | GEO
Project description:Innate immune cells including myeloid cells exhibit dynamic cellular switches during inflammatory and immune responses against infection. These processes are tightly regulated at different levels including the cis-regulatory elements of immune cells. However, it remains unclear how the dynamic states of cis-regulatory elements of innate immune cells are controlled during inflammatory responses. Here we found that histone methylation regulator PTIP orchestrates inflammatory responses of macrophages through regulating acetylation state of enhancers and promoters. Rapid elevated expression of PTIP is observed in primary human and mouse macrophages upon lipopolysaccharide (LPS) stimulation. Loss of PTIP represses transcription of pro-inflammatory genes, and activates expression of anti-inflammatory genes. Mechanistically, we found that, independent of its function in histone methylation, PTIP interacts with acetyltransferase p300 and deacetylase HDACs, and serves as a beacon to recruit them to specific sites of inflammatory genes respectively. PTIP deficiency alters H3K27 acetylation state of cis-regulatory elements of inflammatory genes. Moreover, PTIP and c-JUN shape a positive and feedforward regulatory circuit. In addition, PTIP deletion sustains immunosuppressive function of tumor-associated macrophages (TAMs) and promotes tumor growth. Overall, our findings uncover a critical role of PTIP in altering the acetylation state of cis-regulatory regions and fine-tuning the inflammatory responses of innate immune cells.
2022-12-30 | GSE163463 | GEO
Project description:Mutations in methyl-CpG-binding protein 2 (MeCP2), a major epigenetic regulator, are the predominant cause of Rett syndrome. We previously found that Mecp2-null microglia are deficient in phagocytic ability, and that engraftment of wild-type monocytes into the brain of Mecp2-deficient mice attenuates pathology. We have observed that Mecp2 deficiency is associated with increased levels of histone acetylation at the cis-regulatory regions of the Mecp2-regulated genes in macrophages. We hypothesized that Mecp2 recruits protein complexes containing histone deacetylases (HDACs) to repress the expression of its target genes. Our ChIP-Seq studies in bone-marrow derived macrophages revealed that Mecp2 co-localizes with Ncor2/Hdac3 protein complex at cis-regulatory regions of the target genes. These results suggest a role for Mecp2 in the recruitment and regulation of Ncor2/Hdac3 repressosome that plays a critical role in the regulation of inflammatory responses in macrophages. Examination of NCOR2 and HDAC3 genome-wide location in bone-marrow derived macrophages.
2015-03-31 | E-GEOD-66501 | biostudies-arrayexpress
Project description:The model is first model of tissue level cellular immune responses to H. pylori in the publication, "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas.
Abstract:
Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.
2016-12-01 | MODEL1611160002 | BioModels
Project description:The model is the second model of the publication "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" published in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas.
Abstract:
Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.
2016-12-01 | MODEL1611160001 | BioModels
Project description:Here, using ChIP-seq, we define the NF-κB cistrome which is comprised of 31,070 cis-acting binding sites responsive to LPS-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl-6 deficient macrophages are acutely hypersensitive to lipopolysaccharide (LPS) and, using comparative ChIP-seq analyses, we find that the Bcl-6 and NF-κB cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6 binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements. keywords: Genome-wide location analysis Identification of BCL6 and NFkB binding sites in unstimulated and LPS-stimulated primary bone-marrow derived macrophages.
2010-11-24 | E-GEOD-16723 | biostudies-arrayexpress
Project description:The innate immune system is a two-edged sword; it is absolutely required for host defense against infection, but if left uncontrolled can trigger a plethora of inflammatory diseases. Here we used systems biology approaches to predict and validate a gene regulatory network involving a dynamic interplay between the transcription factors NF-κB, C/EBPδ, and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of Il6 and Cebpd genes and experimentally validated the prediction that the combination of an initiator (NF-κB), an amplifier (C/EBPδ) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately. Experiment Overall Design: Bone marrow-derived macrophages stimulated with LPS for 0, 20, 40, 60, 80, 120, 240 and 360 minutes.
2009-04-04 | E-GEOD-14769 | biostudies-arrayexpress
Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. 4 pairs of THP-1 cells either stimulated with LPS or not This submission represents transcriptome component of study.
2012-03-07 | E-GEOD-32141 | biostudies-arrayexpress
Project description:Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response. 2 pairs of THP-1 cells either stimulated with LPS or not. ChIP using either H3K9/K14Ac, RNA Pol II (phospho S5) or SP1 antibody. This submission represents chip-seq component of study.
2012-03-07 | E-GEOD-32324 | biostudies-arrayexpress
Project description:Currently, the only available vaccine against tuberculosis is Mycobacterium bovis Bacille Calmette-Guérin (BCG). Pulmonary tuberculosis protection provided by the vaccine varies depending on the strain, the patient’s age, and the evaluated population. Although the adaptive immune responses induced by different BCG strains have been widely studied, little conclusive data is available regarding innate immune responses, especially in macrophages. Here, we aimed to characterize the innate immune responses of human THP-1-derived macrophages at the transcriptional level following a challenge with either the BCG Mexico or Phipps strains. After a brief in vitro characterization of the bacterial strains and the innate immune responses, including nitric oxide production and cytokine profiles, we analyzed the mRNA expression patterns and performed pathway enrichment analysis using RNA microarrays. Our results showed that multiple biological processes were enriched, especially those associated with innate inflammatory and antimicrobial responses, including tumor necrosis factor (TNF)-α, type I interferon (IFN), and IFN-. These findings indicated the pro-inflammatory stimulation of macrophages induced by both BCG strains, at the cytokine level and in terms of gene expression. Our results demonstrated that both strains activated the innate immune response, with better modulation induced by BCG Phipps.
2022-04-10 | GSE171961 | GEO