Deletion of Slc9a1 in Cx3cr1+ cells stimulated microglial subcluster CREB1-BDNF signaling and oligodendrocyte crosstalk
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PROVIDER: PRJNA1036225 | ENA |
REPOSITORIES: ENA
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Project description:Microglial Na/H exchanger-1 (NHE1) protein, encoded by Slc9a1, plays a role in white matter demyelination of ischemic stroke brains. In this study, we conducted single cell RNA-seq transcriptome analysis of corpus collosum and external capsule from wild-type (WT) and conditional Slc9a1 knockout (cKO) mice at 3 days post-stroke to study microglia-oligodendrocyte interactions.
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Project description:Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation. Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation.
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Project description:Factors that increase cAMP levels can induce lineage-specific differentiation of glioma cells into astrocyte-like cells. However, the differentiation pattern and underlying mechanisms remain unclear. Here, we find that cAMP/PKA/CREB1-induced miR-221/222 suppression contributes to the neuron-like differentiation of gliomas. cAMP agonists selectively induced neuron- and astrocyte-like but not oligodendrocyte-like differentiation of C6 glioma cells. PKA inhibitors and CREB1 knockout blocked neuron-like differentiation of glioma cells. cAMP inhibited miR-221/222 in a PKA/CREB1 dependent manner. Importantly, both in vitro and in vivo assays demonstrated that transcriptional suppression of miR-221/222 is required for neuronal differentiation of glioma cells. Our findings suggest that increasing cAMP levels can induce bidirectional differentiation of glioma cells. Furthermore, the miR-221/222 cluster acts as an epigenetic brake during glioma differentiation.
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Project description:To screen the genes and pathways regulated by CREB1 in the THP1 monocytes induced by LPS, THP1 monocytes were transfected by CREB1 shRNA and then treated by LPS for 3 hours.
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Project description:CX3CR1, one of the highest expressed genes in microglia in mice and humans, is implicated in numerous microglial functions. However, the molecular mechanisms underlying Cx3cr1 signaling are not well understood. Here, we analyzed transcriptomes of Cx3cr1-deficient microglia under varying conditions by RNA-Seq. In 2 mos mice, Cx3cr1 deletion resulted in the downregulation of a subset of immune-related genes, without substantial epigenetic changes in markers of active chromatin. Surprisingly, Cx3cr1-deficient microglia from young mice exhibited a transcriptome consistent with that of aged Cx3cr1-sufficient animals, suggesting a premature aging transcriptomic signature. Immunohistochemical analysis of microglia in young and aged mice revealed that loss of Cx3cr1 modulates microglial morphology in a compatible fashion. Our results suggest that CX3CR1 may regulate microglial function in part by modulating the expression levels of a subset of inflammatory genes during chronological aging, making Cx3cr1-deficient mice useful for studying aged microglia.
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Project description:CX3CR1, one of the highest expressed genes in microglia in mice and humans, is implicated in numerous microglial functions. However, the molecular mechanisms underlying Cx3cr1 signaling are not well understood. Here, we analyzed transcriptomes of Cx3cr1-deficient microglia under varying conditions by RNA sequencing (RNA-Seq). In 2 mos mice, Cx3cr1 deletion resulted in the downregulation of a subset of immune-related genes, without substantial epigenetic changes in markers of active chromatin. Surprisingly, Cx3cr1-deficient microglia from young mice exhibited a transcriptome consistent with that of aged Cx3cr1-sufficient animals, suggesting a premature aging transcriptomic signature.
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Project description:Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2-/- mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is up-regulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2-/- mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.
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Project description:cAMP responsive element binding protein 1 (CREB1) is a transcription factor belonging to the basic leucine zipper (bZIP) family. Previous studies on the transcriptional regulatory targets of CREB1 have focused on protein-coding genes. The non-coding targets regulated by CREB1 in gastric cancer remain to be further studied. Herein, the genome-wide mapping of CREB1 binding in gastric cancer cell AGS was determined by chromatin immunoprecipitation sequencing.
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Project description:Memory T cells are important for protective immunity against infectious microorganisms. Such protection is achieved by cooperative action of memory T cell populations that differ in their tissue localization and functionality. We report on the identification of the fractalkine receptor CX3CR1 as marker for stratification of memory T cells with cytotoxic effector function from those with proliferative function in both, mice and man. Based on CX3CR1 and CD62L expression levels four distinct memory T cell populations can be distinguished based on their functional properties. Transcriptome and proteome profiling revealed that CX3CR1 expression was superior to CD62L to resolve memory T cell functionality and allowed determination of a core signature of memory T cells with cytotoxic effector function. This identifies a CD62Lhi CX3CR1+ memory T cell population with an identical gene signature to CD62LlowCX3CR1+ effector memory T cells. In lymph nodes, this so far unrecognized CD62LhiCX3CR1+ T cell population shows a distinct migration pattern and anatomic positioning compared to CD62LhiCX3CR1neg TCM. Furthermore, CX3CR1+ memory T cells were scarce or absent during chronic HBV, HCV and HIV infection in man and chronic LCMV infection in mice confirming the value of CX3CR1+ in understanding principles of protective immune memory. CD8+ T cells were isolated and directly assessed or incubated with DC or LSEC. After harvesting, cells were immediately lysed in Trizol (Invitrogen) before storage at -80°C for RNA isolation.
2016-06-10 | E-GEOD-63118 | biostudies-arrayexpress
Project description:During chronic viral infection, pathogen-specifc CD8+ T cells develop into three main phenotypically and functionally distinct subsets: TCF1hi progenitor, PD-1hi exhausted, and recently identied CX3CR1+ cytotoxic effector cells. Although genetic programs governing progenitor and exhausted subset formation have been well-studied, how CX3CR1+ effector CD8+ T cell differentiation is transcriptionally and epigentically regulated remains elusive. In this study, our single cell transcriptomics and epigenetic assays revealed that three subsets of virus-specific cells were governed by distinct gene regulatory networks (GRNs) and epigenetic landscapes. Computational analyses demonstrated a striking similarity between the CX3CR1+ subset and short-live effector cells (SLECs) from acute LCMV infection. Consistently, genetic deletion of T-bet (Tbx21) significantly diminished the formation and function of the CX3CR1+ subset. Importantly, we identify that the transcription factor (TF) BATF is required to maintain a permissive chromatin structure that allows differentiation transition from TCF1+ progenitor to CX3CR1+ effector cells. Intriguingly, haplodificiency of BATF in CD8+ T cells abolished CX3CR1+ effector subset formation. Lastly, we found that BATF directly bound to key genetic regions such as Tbx21 and modulated their enhancer accessibility to facilitate progenitor to CX3CR1+ effector cell transition. These mechanistic insights can be harnessed to overcome T cell exhaustion in treating chronic infections and cancer.
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