Genome-wide profiles of IRF8 and PU.1 bindings, and H3K4me1 and H3K27ac histone marks in wild-type and IRF8-knockout microglia [CHIP-seq]
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PROVIDER: PRJNA964775 | ENA |
REPOSITORIES: ENA
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Project description:The role of the lineage-determining transcription factor Interferon regulatory factor 8 (IRF8) in microglia remains elucidated. Here we report the genome-wide IRF8 binding profiles in microglia at various ages. CUT&RUN methodology revealed that IRF8 starts to bind to the genome around postnatal day 9 (P9), and its number increases with age. In comparison to peritoneal macrophages, microglia IRF8 showed a cell-intrinsic binding pattern. By co-occurrence analysis, most IRF8 was H3K4me1/H3K27ac-marked enhancers, and many of them bind to the H3K27ac(high) super-enhancer regions. In IRF8KO microglia, H3K4me1 and H3K27ac profiles were altered and deposited aberrantly on the genome. This study provides a novel insight into understanding epigenetic regulation in microglia.
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Project description:This SuperSeries is composed of the following subset Series: GSE30357: Chip-chip from human diffuse large B cell lymphoma cell lines with IRF8 GSE30358: Mouse B cell lymphoma cell lines:IRF8 knockdown cells vs. Control GSE30519: Chip-chip from mouse diffuse large B cell lymphoma cell lines with IRF8 GSE30520: Chip-chip from mouse diffuse large B cell lymphoma cell lines with PU.1 Refer to individual Series
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Project description:Chromatins were prepared from myeloid progenitor cell line Tot2 cells transduced with retrovirus for control MSCV or MSCV-IRF8. Chromatin immunoprecipitation (ChIP) was carried out by using anti-IRF8 antibody, anti-PU.1 antibody or anti-histone H3K4me1 antibody. ChIP-Seq peaks were identified using the FindPeaks tool in the HOMER package or SICER with input DNA tags as background distribution. Potential IRF8-direct target genes were identified based on ChIP-Seq and the alteration of expression by IRF8-induction. Examination of 2 transcription factor occupancy and 1 histone modifications in myeloid progenitor cells and monocyte-like cells differetiated by IRF8 expression
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Project description:Chromatins were prepared from myeloid progenitor cell line Tot2 cells transduced with retrovirus for control MSCV or MSCV-IRF8. Chromatin immunoprecipitation (ChIP) was carried out by using anti-IRF8 antibody, anti-PU.1 antibody or anti-histone H3K4me1 antibody. ChIP-Seq peaks were identified using the FindPeaks tool in the HOMER package or SICER with input DNA tags as background distribution. Potential IRF8-direct target genes were identified based on ChIP-Seq and the alteration of expression by IRF8-induction.
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Project description:The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3-/- mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage. Examination of histone modifications (H3K27ac and H3K4me1) and 2 transcription factors (Batf3 and Irf8) and the p300 co-factor binding in 3 different dendritic cell subsets
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Project description:The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune cell development and function. However, the understanding of molecular mechanisms of each family member has been limited due to their redundancy and broad effects on multiple lineages of cells. Here, we report that double deletion of floxed Irf8 and Spi1 (encoding PU.1) by Mb1-Cre (designated DKO mice) in the B cell lineage resulted in severe defects in the development of follicular and germinal center (GC) B cells. Class switch recombination and antibody affinity maturation were also compromised in DKO mice. RNA-seq and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in follicular and activated B cells. DKO B cells had diminished expression of target genes vital for maintaining follicular B cell identity and GC development. Moreover, our findings reveal that expression of BCL6, which is critical for development of germinal center B cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B cells.
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Project description:IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by pro-inflammatory signals such as interferon gamma. Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type, and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all the genes bound by (cistromes) and transcriptionally activated (regulomes) by IRF8, IRF1, PU.1 and STAT1 including modulation of epigenetic histone marks. Of seven binding combinations identified, two (cluster 1: IRF8/IRF1/STAT1/PU.1; cluster 5: IRF1/STAT1/PU.1) were found to have a major role in controlling macrophage transcriptional programs both at basal level and following IFNγ activation. They direct expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and anti-microbial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immuno-deficiencies, and with loci associated for several inflammatory diseases in humans.
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Project description:IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by pro-inflammatory signals such as interferon gamma. Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type, and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all the genes bound by (cistromes) and transcriptionally activated (regulomes) by IRF8, IRF1, PU.1 and STAT1 including modulation of epigenetic histone marks. Of seven binding combinations identified, two (cluster 1: IRF8/IRF1/STAT1/PU.1; cluster 5: IRF1/STAT1/PU.1) were found to have a major role in controlling macrophage transcriptional programs both at basal level and following IFNγ activation. They direct expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and anti-microbial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immuno-deficiencies, and with loci associated for several inflammatory diseases in humans.
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Project description:The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8M-bM-^@M-^SPU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRFM-bM-^@M-^SAP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome. While constitutively expressed IRF8-dependent genes contained only sites mediating basal IRF8/PU.1 recruitment, inducible IRF8-dependent genes contained variable combinations of constitutive and inducible sites. Overall, these data show at the genome scale how the same TF can be linked to constitutive and inducible gene regulation via distinct combinations of alternative DNA-binding sites. Chromatin immuno-precipitations of transcription factors IRF8, IRF1, PU.1, STAT1, STAT2 and of H3 lysine 27 acetylated followed by multiparallel sequencing, performed in bone marrow-derived macrophages from wild type (WT) and BXH2/TyJ mice. Cells were treated with lipopolysaccharide (LPS) for 2 or 4 hours, or interferon b (IFNb) for 30 or 60 minutes, 2 or 4 hours, or left unstimulated.
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Project description:Temporal and spatial gene expression patterns are regulated by enhancer-specific histone modifications H3K4me1 and H3K27ac. To better understand age-dependent alteration of these enhancer marks, we analysed their genome-wide profiles and compared against changes in gene expression in the head tissues harvested from young Day 10 and D50 male Drosophila. The genome-wide binding patterns of H3K4me1 and H3K27ac remain highly similar (>85%) during ageing with marginally higher signals for both marks in older Day 50 flies. Signals were significantly higher in Day 50 flies near the transcription start sites for H3K4me1 whereas for H3K27ac, signals were significantly higher in Day 50 flies globally. Interestingly, analysis using MACS bdgdiff identified “x” H3K4me1 and “y” H3K27ac differential peaks that correlated with distinct sets of age-dependent differential expressed genes (DEG). Most of the H3K4me1 differential peaks (percentage of x) are located within the gene body of DEGs that are associated with RNA and metabolic processes. On the other hand, majority of differential H3K27ac peaks (percentage of y) are located 5 kb upstream of TSS of DEG enriched for various immune responses. Our results suggest that while both enhancer marks do not undergo significant global reconfiguration during aging, they are likely to be involved in activating independent sets of genes through distinct transcription activators.
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