Interferon-γ Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE98369 | GEO | 2017/07/01
SECONDARY ACCESSION(S): PRJNA384911
REPOSITORIES: GEO
Similar Datasets
Project description:Mechanisms by which interferon (IFN)-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription-factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an "M2"-like homeostatic and reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ disassembled a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding enhancers were suppressed in macrophages isolated from rheumatoid-arthritis patients, revealing a disease-associated signature of IFN-γ-mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression and reveal that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-γ to augment macrophage activation.
| S-EPMC5568089 | biostudies-literature
Project description:Interferon-γ Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF
| PRJNA384911 | ENA
Project description:Mechanisms by which IFN-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an ‘M2’-like homeostatic/reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ ‘disassembled’ a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding disassembled enhancers were suppressed in rheumatoid arthritis macrophages, revealing a disease-associated ‘negative IFN-γ signature’. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression, and MAF as a regulator of the macrophage enhancer landscape that is suppressed by IFN-γ to augment macrophage activation.
2017-07-01 | GSE98368 | GEO
Project description:Mechanisms by which IFN-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an ‘M2’-like homeostatic/reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ ‘disassembled’ a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding disassembled enhancers were suppressed in rheumatoid arthritis macrophages, revealing a disease-associated ‘negative IFN-γ signature’. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression, and MAF as a regulator of the macrophage enhancer landscape that is suppressed by IFN-γ to augment macrophage activation.
2017-07-01 | GSE98367 | GEO
Project description:Mechanisms by which IFN-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an ‘M2’-like homeostatic/reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ ‘disassembled’ a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding disassembled enhancers were suppressed in rheumatoid arthritis macrophages, revealing a disease-associated ‘negative IFN-γ signature’. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression, and MAF as a regulator of the macrophage enhancer landscape that is suppressed by IFN-γ to augment macrophage activation.
2017-07-01 | GSE98365 | GEO
Project description:The transcription factor GATA3 is crucial for the differentiation of naive CD4(+) T cells into T helper 2 (Th2) cells. Here, we show that deletion of Gata3 allowed the appearance of interferon-gamma (IFN-gamma)-producing cells in the absence of interleukin-12 (IL-12) and IFN-gamma. Such IFN-gamma production was transcription factor T-bet independent. Another T-box-containing transcription factor Eomes, but not T-bet, was induced both in GATA3-deficient CD4(+) T cells differentiated under Th2 cell conditions and in Th2 cells with enforced Runx3 expression, contributing to IFN-gamma production. GATA3 overexpression blocked Runx3-mediated Eomes induction and IFN-gamma production, and GATA3 protein physically interacted with Runx3 protein. Furthermore, we found that Runx3 directly bound to multiple regulatory elements of the Ifng gene and that blocking Runx3 function in either Th1 or GATA3-deficient "Th2" cells results in diminished IFN-gamma production by these cells. Thus, the Runx3-mediated pathway, actively suppressed by GATA3, induces IFN-gamma production in a STAT4- and T-bet-independent manner.
| S-EPMC2867662 | biostudies-literature
Project description:Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.
| S-EPMC7108920 | biostudies-literature
Project description:IL-10 is an important immunoregulatory factor. However, our understanding of IL-10 gene regulation remains very limited. In this study, following up on our previous novel finding that the protooncogene c-Maf of the basic leucine zipper family of transcription factors is expressed in monocytes and macrophages, we investigate the role of c-Maf in the transcriptional regulation of IL-10 and the underlying molecular mechanism in macrophages. c-Maf-null macrophages exhibit strongly impaired IL-10 protein production and mRNA expression upon LPS stimulation. Ectopic expression of c-Maf stimulates not only exogenously transfected IL-10 promoter-driven luciferase activity in a dose-dependent manner but also enhances endogenous IL-10 gene expression stimulated by LPS. Both in vitro and in vivo experiments identify a c-Maf response element localized to nucleotides -196/-184 relative to the transcription initiation site in the IL-10 promoter. This site represents an atypical 12-O-tetradecanoate-13-acetate-responsive element for musculoaponeurotic fibrosarcoma recognition and functions as an enhancer element in a heterologous and orientation-independent manner. Furthermore, c-Maf is expressed constitutively in resting monocytes/macrophages. IL-4 can up-regulate c-Maf expression, its binding to IL-10 promoter, and dose dependently enhance IL-10 production induced by LPS; moreover, IL-4 failed to enhance LPS-induced IL-10 production in c-Maf-null macrophages. Taken together, these data demonstrate that c-Maf is an indispensable yet constitutive transcription factor for IL-10 gene expression in LPS-activated macrophages, and IL-4 modulates IL-10 production in inflammatory macrophages likely via its ability to induce c-Maf expression. Thus, this study uncovers a novel and important function of c-Maf in macrophages and elucidates its transcriptional mechanism in the regulation of IL-10 gene expression.
| S-EPMC2955976 | biostudies-literature
Project description:In spite of short-day (SD) nature, rice (Oryza sativa) shares a conserved photoperiodic network for flowering control with long-day plants like Arabidopsis thaliana. Flowering or heading is an important agronomic trait in rice. NAC transcription factors (TFs) are well-conserved and one of the largest families of plant TFs. However, their function in flowering or heading time is not well-known yet. A preferential expression of a membrane-bound NAC-like TF OsNTL5 in developing leaves and panicles of rice indicated to us its putative role in flowering. To examine its function, three independent constructs was generated, one with a deletion in the C terminus membrane-spanning domain (OsNTL5∆C), OsNTL5∆C fused with the SRDX transcriptional repressor motif and OsNTL5∆C used with the VP16 activation domain under the Ubiquitin promoter to produce the overexpressing lines OsNTL5∆C, OsNTL5∆C-SRDX, and OsNTL5∆C-VP, respectively in rice. The OsNTL5∆C-VP line showed an early-flowering phenotype. In contrast to this, the plants with OsNTL5∆C and OsNTL5∆C-SRDX showed a very strong late-flowering phenotype, suggesting that OsNTL5 suppresses flowering as a transcriptional repressor. The protein subcellular localization assay suggested that N-terminal part of the OsNTL5 is localized to the nucleus after the protein is cleaved from its membrane-spanning domain at the C-terminal end and functions as a TF. Expression of flowering genes responsible for day length signals such as Early Heading Date 1 (Ehd1), Heading Date 3a (Hd3a), and Rice Flowering Locus T1 (RFT1) was significantly changed in the overexpression lines of OsNTL5∆C-VP, OsNTL5∆C, and OsNTL5∆C-SRDX as analyzed by Quantitative Real-time PCR. ChIP-qPCR and rice protoplasts assays indicate that OsNTL5 directly binds to the promoter of Ehd1 and negatively regulates the expression of Ehd1, which shows antagonistic photoperiodic expression patterns of OsNTL5 in a 24-h SD cycle. Hence in conclusion, the NAC-like TF OsNTL5 functions as a transcriptional repressor to suppress flowering in rice as an upstream factor of Ehd1.
| S-EPMC5943572 | biostudies-literature
Project description:The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma-C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.
| S-EPMC10954715 | biostudies-literature