Mechanisms Controlling Human Microglia Gene Expression
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PROVIDER: PRJNA388723 | ENA |
REPOSITORIES: ENA
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Project description:Mechanisms Controlling Human Microglia Gene Expression
| PRJNA388724 | ENA
Project description:Microglia isolated from glioma patients gain anti-tumor activities upon poly (I:C) stimulation. Expression profiles of human tumor-infiltrating microglia/macrophages before (untreated) and after treatment with poly (I:C) for 48h (induced). Tumor-infiltrating microglia/macrophages were isolated from freshly excised brain tumors
2011-12-31 | E-GEOD-25289 | biostudies-arrayexpress
Project description:Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1 and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.
2024-01-26 | PXD046040 | Pride
Project description:Hepatocyte nuclear factor 4alpha (HNF-4alpha) (nuclear receptor 2A1) is an essential regulator of hepatocyte differentiation and function. Genetic and molecular evidence suggests that the tissue-restricted expression of HNF-4alpha is regulated mainly at the transcriptional level. As a step toward understanding the molecular mechanism involved in the transcriptional regulation of the human HNF-4alpha gene, we cloned and analyzed a 12.1-kb fragment of its upstream region. Major DNase I-hypersensitive sites were found at the proximal promoter, the first intron, and the more-upstream region comprising kb -6.5, -8.0, and -8.8. By the use of reporter constructs, we found that the proximal-promoter region was sufficient to drive high levels of hepatocyte-specific transcription in transient-transfection assays. DNase I footprint analysis and electrophoretic mobility shift experiments revealed binding sites for HNF-1alpha and -beta, Sp-1, GATA-6, and HNF-6. High levels of HNF-4alpha promoter activity were dependent on the synergism between either HNF-1alpha and HNF-6 or HNF-1beta and GATA-6, which implies that at least two alternative mechanisms may activate HNF-4alpha gene transcription. Chromatin immunoprecipitation experiments with human hepatoma cells showed stable association of HNF-1alpha, HNF-6, Sp-1, and COUP-TFII with the promoter. The last factor acts as a repressor via binding to a newly identified direct repeat 1 (DR-1) sequence of the human promoter, which is absent in the mouse homologue. We present evidence that this sequence is a bona fide retinoic acid response element and that HNF-4alpha expression is upregulated in vivo upon retinoic acid signaling.
| S-EPMC99906 | biostudies-literature
Project description:Iron accumulation in microglia has been observed in Alzheimer’s disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms including neuroinflammation. To study the interaction between iron accumulation and inflammation, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with an increasing concentration of iron, in combination with inflammatory stimuli such as interferon gamma and amyloid β, and performed RNA sequencing.
| EGAS00001006112 | EGA
Project description:Single-cell analysis of human retina identifies evolutionarily conserved and species-specific mechanisms controlling development
| PRJNA477287 | ENA
Project description:Single-cell analysis of human retina identifies evolutionarily conserved and species-specific mechanisms controlling development
| PRJNA507018 | ENA
Project description:A human Pluripotent Stem Cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response Walther Haenseler, Stephen N. Sansom, Julian Buchrieser, Sarah E. Newey, Craig S. Moore, Francesca J. Nicholls, Satyan Chintawar, Christian Schnell, Jack P. Antel, Nicholas D. Allen, M. Zameel Cader, Richard Wade-Martins, William S. James, Sally A. Cowley The aim of the experiment was to compare the gene expression profiles from human iPSC-derived embryonic macrophages (both precursors, mature, and cells cultured in 'microglia medium'), with iPSC-macrophages differentiated to microglia by co-culture with iPSC-derived cortical neurons. They were also compared to human blood-derived monocytes and to human primary fetal microglia.
2016-11-14 | GSE89795 | GEO
Project description:Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. Although dysregulation of microglia activity is genetically linked to neurodegenerative and behavioral diseases, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We report here on the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue, revealing broad similarities but also significant differences with mouse microglia. Many genes associated with risk alleles for neurodegenerative diseases are preferentially or highly expressed in human microglia. The transition of human and mouse microglia from the brain to a tissue culture environment results in rapid and extensive downregulation of genes that are induced in primitive mouse macrophages following migration into the fetal brain. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and will facilitate efforts to better understand the roles of microglia in human disease.
2017-05-25 | GSE89960 | GEO
Project description:SPEACC-seq is a novel high-throughput method which enables forward genetic screens to identify cell-cell interaction mechanisms that uncovered an astrocyte-microglia regulatory circuit mediated by amphiregulin and IL33-ST2. signaling. Cell-cell interactions in the central nervous system (CNS) play central roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. For example, several factors mediate microglia-astrocyte interactions that promote CNS pathology, but less is known about regulatory interactions that limit tissue pathology. Here we report the development of SPEACC-seq (Stimulation, Perturbation, and Encapsulation of interACting Cells followed by Sequencing), a forward genetic screening platform which combines genome-wide CRISPR/Cas9 perturbations, cell co-culture in picoliter droplets, and microfluidic-based fluorescence activated droplet sorting to identify mechanisms of cell-cell communication. Using SPEACC-seq in combination with an in vivo perturb-seq screen, we identified microglia-produced amphiregulin as a suppressor of disease promoting astrocyte responses in experimental autoimmune encephalomyelitis (EAE), a pre-clinical model of multiple sclerosis (MS). The production of microglial amphiregulin was induced via ST2 signaling by IL-33 released from astrocytes during EAE. Indeed, the genetic inactivation of ST2 or amphiregulin in microglia, or IL-33 or amphiregulin signaling in astrocytes resulted in the worsening of EAE, suggesting that IL-33-induced microglial amphiregulin limits disease-promoting astrocyte responses associated with CNS pathology. This regulatory loop was also detected in human astrocytes and microglia both in vitro and in MS patient CNS samples. In summary, we developed SPEACC-seq, a high-throughput, droplet-based forward genetic screening platform for the identification of cell-cell interaction mechanisms, which identified a novel microglia-astrocyte negative feedback loop that limits CNS pathology.
2023-11-23 | GSE218732 | GEO