Injury-induced enhancer remodelling in spinal microglia - a novel mechanism for pain chronification?
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ABSTRACT:
PROVIDER: PRJNA290434 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2120300_1.fastq.gz | Fastqsanger.gz | |||
| SRR2120300_2.fastq.gz | Fastqsanger.gz | |||
| SRR2120320_1.fastq.gz | Fastqsanger.gz | |||
| SRR2120320_2.fastq.gz | Fastqsanger.gz | |||
| SRR2120330_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic pain is common and devastating. Yet, its precise molecular origins remain unclear. The condition induces well-characterised changes in neurons and microglia, but it is unknown why they persist long after the precipitating injury has healed. We posit a role for enhancers - regions of open chromatin that define a cell’s transcription factor binding profile. Enhancer profiles can alter upon environmental stimulation, functioning as a kind of molecular memory. Here, a mouse model of persistent neuropathic pain was used to examine microglial enhancers with flow cytometry and sequencing. We observed injury-specific alterations of enhancers in close proximity to transcriptionally regulated genes. Our data also shine light on details relating to the spinal cord immune response and provide the first genome-wide gene expression profile of isolated microglia in a pain state. We hypothesise that enhancer deposition may constitute a novel mechanism by which painful experiences are encoded on a molecular level.
2016-05-12 | GSE71134 | GEO
Project description:Chronic pain is common and devastating. Yet, its precise molecular origins remain unclear. The condition induces well-characterised changes in neurons and microglia, but it is unknown why they persist long after the precipitating injury has healed. We posit a role for enhancers - regions of open chromatin that define a cell’s transcription factor binding profile. Enhancer profiles can alter upon environmental stimulation, functioning as a kind of molecular memory. Here, a mouse model of persistent neuropathic pain was used to examine microglial enhancers with flow cytometry and sequencing. We observed injury-specific alterations of enhancers in close proximity to transcriptionally regulated genes. Our data also shine light on details relating to the spinal cord immune response and provide the first genome-wide gene expression profile of isolated microglia in a pain state. We hypothesise that enhancer deposition may constitute a novel mechanism by which painful experiences are encoded on a molecular level.
2016-05-12 | GSE71133 | GEO
Project description:Neuropathic pain is a prevalent and debilitating chronic disease that is characterized by activation in glial cells in various pain-related regions within the central nervous system. Recent studies have suggested a sexually dimorphic role of microglia in the maintenance of neuropathic pain in rodents. Here, we utilized RNA sequencing analysis of microglia to identify whether there is a common neuropathic microglial signature and characterize the sex differences in microglia in pain-related regions in nerve injury and chemotherapy-induced peripheral neuropathy mouse models. Whilst mechanical allodynia and behavioral changes were observed in all models, transcriptomic analysis of microglia revealed no common transcriptional changes in spinal and supraspinal regions and in different neuropathic models. However, there was a substantial change in microglial gene expression within the ipsilateral lumbar spinal cord 7-days after chronic constriction injury (CCI) of the sciatic nerve. Both sexes upregulated genes associated with inflammation, phagosome, and lysosome activation, though males revealed a prominent global transcriptional shift not observed in female mice. This study demonstrates a lack of a common neuropathic microglial signature and indicates distinct sex differences in spinal microglia, suggesting they contribute to the sex-specific pain processing following nerve injury.
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Project description:Microglia activation contributes to the development of neuropathic pain. To identify changes of microglial gene expression during their activation after peripheral nerve injury, we employed microarray analysis of individually collected pools of 10 spinal microglia cells
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Project description:Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unknown whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Here, we demonstrate, using single-cell RNA-sequencing, that microglia transcriptional states differ at early and late time points following nerve injury. Male microglia show more proliferation and distinct transcriptional changes in response to nerve injury comparing to females. Apolipoprotein E (Apoe) was the top upregulated gene in microglia at chronic time points after nerve injury in mice and polymorphisms in the APOE in humans are associated with chronic pain. Single-cell analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia and identify a previously unrecognized role for ApoE in neuropathic pain.
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Project description:Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible, genetic microglial depletion strategy at both acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting pain model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain which coincided with the timeframe of full repopulation of microglia after transient microglial depletion at the acute-to-chronic phase. These repopulated microglia were morphologically distinct from control microglia, signifying they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene coexpression network analysis (WGCNA). We intersected these genes with a newly generated single nuclei microglial dataset from human spinal cord dorsal horn and identified human-relevant genes that may ultimately promote pain resolution after injury. This work presents a novel approach to gene discovery in pain and provides comprehensive datasets for the development of future microglial-targeted therapeutics.
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Project description:Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible, genetic microglial depletion strategy at both acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting pain model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain which coincided with the timeframe of full repopulation of microglia after transient microglial depletion at the acute-to-chronic phase. These repopulated microglia were morphologically distinct from control microglia, signifying they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene coexpression network analysis (WGCNA). We intersected these genes with a newly generated single nuclei microglial dataset from human spinal cord dorsal horn and identified human-relevant genes that may ultimately promote pain resolution after injury. This work presents a novel approach to gene discovery in pain and provides comprehensive datasets for the development of future microglial-targeted therapeutics.
2023-12-05 | GSE248983 | GEO
Project description:Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible, genetic microglial depletion strategy at both acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting pain model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain which coincided with the timeframe of full repopulation of microglia after transient microglial depletion at the acute-to-chronic phase. These repopulated microglia were morphologically distinct from control microglia, signifying they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene coexpression network analysis (WGCNA). We intersected these genes with a newly generated single nuclei microglial dataset from human spinal cord dorsal horn and identified human-relevant genes that may ultimately promote pain resolution after injury. This work presents a novel approach to gene discovery in pain and provides comprehensive datasets for the development of future microglial-targeted therapeutics.
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Project description:Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naïve mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia nor reversed CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
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