Radial glia promote microglial development through aVb8 -TGFb1 signaling [ATAC-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE242219 | GEO | 2024/09/02
REPOSITORIES: GEO
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Project description:In this study, we aimed to identify 1) The relevant Itgb8 expressing cell types that mediate microglial TGFb activation; 2) The developmental timing of Itgb8-mediated TGFb signaling in microglia; 3) The cellular source and identity of the TGFb ligand relevant for microglial development and homeostasis; 4) The relationship between developmentally disrupted microglia and disease associated microglia; and 5) The role of canonical (Smad-mediated) versus non-canonical TGFb signaling in microglia.
2024-09-02 | GSE242220 | GEO
Project description:Radial glia promote microglial development through aVb8 -TGFb1 signaling
| PRJNA1012101 | ENA
Project description:Radial glia promote microglial development through aVb8 -TGFb1 signaling [ATAC-seq]
| PRJNA1012104 | ENA
Project description:Radial glia promote microglial development through aVb8 -TGFb1 signaling [ChIP-seq]
| PRJNA1012105 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-09-02 | GSE242221 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226091 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226090 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226089 | GEO
Project description:Spalt-Like Transcription Factor 1 (Sall1) is a critical regulator of organogenesis and microglia identity. Despite its known biological importance, mechanisms that specify the cell-specific expression of Sall1 and its transcriptional functions remain poorly understood. Here, we demonstrate that targeted deletion of a conserved microglia-specific super enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia, thereby identifying an essential regulatory element that transduces brain environmental signals required for microglia-specific gene expression. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knock out (EKO) mice to probe how SALL1 shapes the regulatory landscape of microglia, we provide evidence that SALL1 functions to both directly activate microglia-specific genes and repress genes that are associated with inflammation and aging. Unexpectedly, motifs for SMAD proteins that mediate transcriptional effects of TGFb signaling were enriched within the set of enhancers predicted to be directly activated by SALL1, suggesting that collaborative interactions between SALL1 and SMADs are required to establish microglia-specific gene expression. To test this hypothesis, we determined the transcriptional consequences of a conditional knockout of the common co-SMAD Smad4 and defined the genome-wide locations of SMAD4 in wild type and EKO microglia. These studies revealed two layers of functional interdependence. First, we found that SMAD4 binds directly to the Sall1 super enhancer and is required for Sall1 expression, consistent with the requirement of the TGFb and SMAD homologues Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Second, we extend this paradigm by demonstrating that SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in EKO microglia. Collectively, these results suggest molecular mechanisms by which SALL1 enforces microglia-specific functions of the TGFb-SMAD signaling axis that may be relevant to roles of SALL1 in other developmental contexts.
2023-05-01 | GSE226088 | GEO
Project description:Background Proteomic characterization of microglia has been limited by low yield and contamination by non-microglial proteins by magnetic-activated cell sorting (MACS) enrichment strategies. To determine whether a fluorescent-activated cell sorting (FACS)-based strategy overcomes these limitations, we compared microglial proteomes of MACS and FACS-based purified CD11b+ microglia in order to identify core sets of microglial proteins in adult mouse brain tissue. Results Quantitative multiplex proteomics by tandem mass tag mass spectrometry (TMT-MS) of MACS-enriched (N = 5) and FACS-purified (N = 5) adult wild-type CD11b+ microglia identified 1,791 proteins, of which 953 were differentially expressed indicating significant differences between both approaches. While the FACS-purified microglia proteome was enriched with cytosolic, endoplasmic reticulum and ribosomal proteins involved in protein metabolism and immune system functions, the MACS-enriched microglia proteome was enriched with proteins related to mitochondrial function and synaptic transmission. As compared to MACS, the FACS microglial proteome showed strong enrichment for canonical microglial proteins while neuron, astrocyte, and oligodendrocyte proteins were decreased. Interestingly, we observed enrichment of endothelial specific proteins in the FACS microglia proteome. By comparing FACS-purified microglia proteomes with transcriptomes, we observed highly concordant as well as highly discordant proteins that were abundant at the protein level but low at the transcript level. Conclusions We demonstrate that TMT-MS proteomics of FACS-purified adult microglia is superior to column-based enrichment approaches, resulting in purer and highly-enriched microglial proteomes. We also define core sets of highly-abundant adult microglial proteins including Moesin (Msn) that can guide future studies.
2020-05-11 | PXD015652 | Pride