Similar Datasets
Project description:Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. The transcription factor Ikaros has been shown to play a critical role in lymphoid cell development and differentiation; however, its function in myeloid cells and innate immune responses is less appreciated. Using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility, we describe unexpected dual repressor and activator functions for Ikaros in the LPS response of murine macrophages. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1-/- macrophages showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of many delayed LPS response genes, and chromatin immunoprecipitation sequencing analyses support a key role for Ikaros in sustained NF-?B chromatin binding. Decreased Ikaros expression in Ikzf1+/- mice and human cells dampens these Ikaros-enhanced inflammatory responses, highlighting the importance of quantitative control of Ikaros protein level for its activator function. In the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin remodeling, gene expression, and cytokine responses. Together, our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge.
| S-EPMC6069956 | biostudies-literature
Project description:Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. Here we describe an unexpected role for the lymphoid lineage-determining factor Ikaros in the macrophage LPS response using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility. Ikaros exhibited dual repressor and activator roles in LPS-induced gene expression. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1-/- cells showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of delayed response genes and ChIP-seq analyses support a key role for Ikaros in sustained NF-kB chromatin binding. Furthermore, in the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin dynamics, gene expression, and cytokine responses. Our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge.
2018-06-26 | GSE93600 | GEO
Project description:Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. Here we describe an unexpected role for the lymphoid lineage-determining factor Ikaros in the macrophage LPS response using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility. Ikaros exhibited dual repressor and activator roles in LPS-induced gene expression. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1-/- cells showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of delayed response genes and ChIP-seq analyses support a key role for Ikaros in sustained NF-kB chromatin binding. Furthermore, in the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin dynamics, gene expression, and cytokine responses. Our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge.
2018-06-26 | GSE93599 | GEO
Project description:Macrophage activation by bacterial LPS leads to induction of a complex inflammatory gene program dependent on numerous transcription factor families. Here we describe an unexpected role for the lymphoid lineage-determining factor Ikaros in the macrophage LPS response using comprehensive genomic analysis of Ikaros-dependent transcription, DNA binding, and chromatin accessibility. Ikaros exhibited dual repressor and activator roles in LPS-induced gene expression. Consistent with the described function of Ikaros as transcriptional repressor, Ikzf1-/- cells showed enhanced induction for select responses. In contrast, we observed a dramatic defect in expression of delayed response genes and ChIP-seq analyses support a key role for Ikaros in sustained NF-kB chromatin binding. Furthermore, in the absence of Ikaros, a constitutively open chromatin state was coincident with dysregulation of LPS-induced chromatin dynamics, gene expression, and cytokine responses. Our data suggest a central role for Ikaros in coordinating the complex macrophage transcriptional program in response to pathogen challenge.
2018-06-26 | GSE93598 | GEO
Project description:Genome-wide analysis reveals dual roles for Ikaros in regulation of macrophage chromatin state and inflammatory gene expression
| PRJNA361260 | ENA
Project description:Cell cycle (CC) facilitates cell division via robust, cyclical gene expression. Protective immunity requires the expansion of pathogen-responsive cell types, but whether CC confers unique gene expression programs that direct the subsequent immunological response remains unclear. Here, we demonstrate that single macrophages (MFs) adopt different plasticity states in CC, which leads to heterogeneous cytokine-induced polarization, priming, and repolarization programs. Specifically, MF plasticity to interferon gamma (IFNG) is substantially reduced during S-G2/M, whereas interleukin 4 (IL-4) induces S-G2/M-biased gene expression, mediated by CC-biased enhancers. Additionally, IL-4 polarization shifts the CC-phase distribution of MFs toward the G2/M phase, providing a subpopulation-specific mechanism for IL-4-induced, dampened IFNG responsiveness. Finally, we demonstrate CC-dependent MF responses in murine and human disease settings in vivo, including Th2-driven airway inflammation and pulmonary fibrosis, where MFs express an S-G2/M-biased tissue remodeling gene program. Therefore, MF inflammatory and regenerative responses are gated by CC in a cyclical, phase-dependent manner.
| S-EPMC9831293 | biostudies-literature
Project description:Memory lymphocytes are characterized by their ability to exhibit a rapid response to the recall antigen, in which differential transcription is important, yet the underlying mechanism is not understood. We report here a genome-wide analysis of histone methylation on two histone H3 lysine residues (H3K4me3 and H3K27me3) and gene expression profiles in naive and memory CD8(+) T cells. We found that specific correlation exists between gene expression and the amounts of H3K4me3 (positive correlation) and H3K27me3 (negative correlation) across the gene body. These correlations displayed four distinct modes (repressive, active, poised, and bivalent), reflecting different functions of these genes in CD8(+) T cells. Furthermore, a permissive chromatin state of each gene was established by a combination of different histone modifications. Our findings reveal a complex regulation by histone methylation in differential gene expression and suggest that histone methylation may be responsible for memory CD8(+) T cell function.
| S-EPMC2709841 | biostudies-literature
Project description:OBJECTIVE:Human macrophages can shift phenotype across the inflammatory M1 and reparative M2 spectrum in response to environmental challenges, but the mechanisms promoting inflammatory and cardiometabolic disease-associated M1 phenotypes remain incompletely understood. Alternative splicing (AS) is emerging as an important regulator of cellular function, yet its role in macrophage activation is largely unknown. We investigated the extent to which AS occurs in M1 activation within the cardiometabolic disease context and validated a functional genomic cell model for studying human macrophage-related AS events. APPROACH AND RESULTS:From deep RNA-sequencing of resting, M1, and M2 primary human monocyte-derived macrophages, we found 3860 differentially expressed genes in M1 activation and detected 233 M1-induced AS events; the majority of AS events were cell- and M1-specific with enrichment for pathways relevant to macrophage inflammation. Using genetic variant data for 10 cardiometabolic traits, we identified 28 trait-associated variants within the genomic loci of 21 alternatively spliced genes and 15 variants within 7 differentially expressed regulatory splicing factors in M1 activation. Knockdown of 1 such splicing factor, CELF1, in primary human macrophages led to increased inflammatory response to M1 stimulation, demonstrating CELF1's potential modulation of the M1 phenotype. Finally, we demonstrated that an induced pluripotent stem cell-derived macrophage system recapitulates M1-associated AS events and provides a high-fidelity macrophage AS model. CONCLUSIONS:AS plays a role in defining macrophage phenotype in a cell- and stimulus-specific fashion. Alternatively spliced genes and splicing factors with trait-associated variants may reveal novel pathways and targets in cardiometabolic diseases.
| S-EPMC4919157 | biostudies-literature
Project description:Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of DeltaFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine-including a new role for sirtuins (Sirt1 and Sirt2)-which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.
| S-EPMC2779727 | biostudies-literature
Project description:BackgroundHistone post-translational modifications (PTMs) play central roles in chromatin-templated processes. Combinations of two or more histone PTMs form unique interfaces for readout and recruitment of chromatin interacting complexes, but the genome-wide mapping of coexisting histone PTMs remains an experimentally difficult task.ResultsWe introduce here a novel type of affinity reagents consisting of two fused recombinant histone modification interacting domains (HiMIDs) for direct detection of doubly modified chromatin. To develop the method, we fused the MPP8 chromodomain and DNMT3A PWWP domain which have a binding specificity for H3K9me3 and H3K36me2/3, respectively. We validate the novel reagent biochemically and in ChIP applications and show its specific interaction with H3K9me3-H3K36me2/3 doubly modified chromatin. Modification specificity was confirmed using mutant double-HiMIDs with inactivated methyllysine binding pockets. Using this novel tool, we mapped coexisting H3K9me3-H3K36me2/3 marks in human cells by chromatin interacting domain precipitation (CIDOP). CIDOP-seq data were validated by qPCR, sequential CIDOP/ChIP and by comparison with CIDOP- and ChIP-seq data obtained with single modification readers and antibodies. The genome-wide distribution of H3K9me3-H3K36me2/3 indicates that it represents a novel bivalent chromatin state, which is enriched in weakly transcribed chromatin segments and at ZNF274 and SetDB1 binding sites.ConclusionsThe application of double-HiMIDs allows the single-step study of co-occurrence and distribution of combinatorial chromatin marks. Our discovery of a novel H3K9me3-H3K36me2/3 bivalent chromatin state illustrates the power of this approach, and it will stimulate numerous follow-up studies on its biological functions.
| S-EPMC5613355 | biostudies-literature