Microglia transcriptome in a rat model of ischemic stroke
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE148350 | GEO | 2020/04/24
REPOSITORIES: GEO
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Project description:The rapid accumulation of self-renewed polarized microglia in the penumbra is the critical neuroinflammatory process after the onset of ischemic stroke, leading to secondary demyelination and neuronal loss. HDAC3 has been reported to regulate cell proliferation of tumour cells and modulate neuroinflammation. However, the mechanism by which HDAC3 regulates microgliosis and microglial polarization remains ambiguous. Herein, we demonstrated that microglia-specific ablation of HDAC3 (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. Starting with unbiased RNA seq of microglia, we identified mitosis as the most significant process reversed by loss of HDAC3. Notably, HDAC3-miKO specifically inhibited the proliferation of M1-like microglia but not M2-like microglia, resulting in microglial transition to an M1-like state. Moreover, ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) revealed that HDAC3 deletion induced drastic closing of accessible regions enriched with motifs for PU.1. Taken together, we uncovered for the first time that HDAC3/PU.1-mediated differential proliferation-related reprogramming in different microglia populations drives poststroke inflammatory state transition of microglia and thereby contributes to the pathophysiology of ischemic stroke.
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Project description:The rapid accumulation of self-renewed polarized microglia in the penumbra is the critical neuroinflammatory process after the onset of ischemic stroke, leading to secondary demyelination and neuronal loss. HDAC3 has been reported to regulate cell proliferation of tumour cells and modulate neuroinflammation. However, the mechanism by which HDAC3 regulates microgliosis and microglial polarization remains ambiguous. Herein, we demonstrated that microglia-specific ablation of HDAC3 (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. Starting with unbiased RNA seq of microglia, we identified mitosis as the most significant process reversed by loss of HDAC3. Notably, HDAC3-miKO specifically inhibited the proliferation of M1-like microglia but not M2-like microglia, resulting in microglial transition to an M1-like state. Moreover, ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) revealed that HDAC3 deletion induced drastic closing of accessible regions enriched with motifs for PU.1. Taken together, we uncovered for the first time that HDAC3/PU.1-mediated differential proliferation-related reprogramming in different microglia populations drives poststroke inflammatory state transition of microglia and thereby contributes to the pathophysiology of ischemic stroke.
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Project description:Senescence-associated alterations in microglia may have profound impact on cerebral homeostasis and stroke outcomes. However, the lack of a transcriptome-wide comparison between young and aged microglia in the context of ischemia limits our understanding of aging-related mechanisms. Herein, we performed bulk RNA sequencing analysis of microglia purified from cerebral hemispheres of young adult (10-week-old) and aged (18-month-old) mice 5 days after distal middle cerebral artery occlusion or sham operation. Considerable transcriptional differences were observed between young and aged microglia in healthy brains, indicating heightened chronic inflammation in aged microglia. Following stroke, the overall transcriptional activation was more robust in young microglia than in aged microglia. Gene clusters with functional implications in immune inflammatory responses, immune cell chemotaxis, tissue remodeling, and cell-cell interactions were markedly activated in microglia of young but not aged stroke mice. These alterations in microglial gene response may contribute to aging-driven vulnerability and poorer recovery after ischemic stroke.
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Project description:Microglial activation after stroke may lead to development of inflammation-induced brain damage. Here we uncover a ribosome-based mechanism/check point involved in control of the innate immune response and microglial activation orchestrated by RNA binding protein SRSF3. Using an in vivo model-system for analysis of the dynamic translational state of microglial ribosomes with mRNAs as input and newly synthesized peptides as an output, we found a marked dissociation of microglia mRNA and protein signatures following ischemic stroke. Highly up-regulated and ribosomes associated mRNAs were not translated 24hrs after stroke resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA and immunomodulatory/homeostatic protein signatures. We found that this is due to specific translational suppression of highly expressed mRNAs through a 3'UTR-mediated mechanism involving the RNA binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia after stroke.
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