Microglia-specific transcriptional repression of interferon-regulated genes after prolonged stress in mice

Zhang, Yuan; Dong, Yuhao; Zhu, Yueyan; Sun, Daijing; Wang, Shunying; Jie, Weng; Zhu, Yue; Peng, Wenzhu; Yu, Bo; Jiang, Yan

doi:10.1016/j.ynstr.2022.100495

Cited by 11 publications

(14 citation statements)

References 76 publications

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“…Ciita, Ifng, H2-Aa, Oasl2, Gbp8, I 213, I 27l2a, Tgtp2) or 24 hours (e.g. I tm3, Irf7) following LPS treatment, aligning with patterns also observed in long-term/chronic stress models (Sonnenfeld, Cunnick et al 1992, Zhang, Dong et al 2022). In the DJ-1 mutant iMG, S100A6, NLRP2 and ACOD1 were among the most downregulated genes, both at baseline and after LPS treatment.…”

Section: Discussionsupporting

confidence: 78%

PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

Mogensen,

Sousa,

Ameli

et al. 2024

Preprint

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Background Specific microglia responses are thought to contribute to the development and progression of neurodegenerative diseases, including Parkinson’s disease (PD). However, the phenotypic acquisition of microglial cells and their role during the underlying neuroinflammatory processes remain largely elusive. Here, according to the multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination of genetics and various environmental risk factors, we investigate microglial transcriptional programs and morphological adaptations under PARK7/DJ-1 deficiency, a genetic cause of PD, during lipopolysaccharide (LPS)-induced inflammation. Methods Using a combination of single-cell RNA-sequencing, bulk RNA-sequencing, multicolor flow cytometry and immunofluorescence analyses, we comprehensively compared microglial cell phenotypic characteristics in PARK7/DJ-1 knock-out (KO) with wildtype littermate mice following 6- or 24-hour intraperitoneal injection with LPS. For translational perspectives, we conducted corresponding analyses in human PARK7/DJ-1 mutant induced pluripotent stem cell (iPSC)-derived microglia and murine bone marrow-derived macrophages (BMDMs). Results By excluding the contribution of other immune brain resident and peripheral cells, we show that microglia acutely isolated from PARK7/DJ-1 KO mice display a distinct phenotype, specially related to type II interferon and DNA damage response signaling, when compared with wildtype microglia, in response to LPS. We also detected discrete signatures in human PARK7/DJ-1 mutant iPSC-derived microglia and BMDMs from PARK7/DJ-1 KO mice. These specific transcriptional signatures were reflected at the morphological level, with microglia in LPS-treated PARK7/DJ-1 KO mice showing a less amoeboid cell shape compared to wildtype mice, both at 6 and 24 hours after acute inflammation, as also observed in BMDMs. Conclusions Taken together, our results show that, under inflammatory conditions, PARK7/DJ-1 deficiency skews microglia towards a distinct phenotype characterized by downregulation of genes involved in type II interferon signaling and a less prominent amoeboid morphology compared to wildtype microglia. These findings suggest that the underlying oxidative stress associated with the lack of PARK7/DJ-1 affects microglia neuroinflammatory responses, which may play a causative role in PD onset and progression.

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Section: Discussionsupporting

confidence: 78%

PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

Mogensen,

Sousa,

Ameli

et al. 2024

Preprint

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“…Consistent with our findings, bulk-tissue 9 and single-nucleus 20 RNA-seq in the DLPFC revealed downregulation of genes associated with inflammatory cytokines, microglia– activation, and immune-signaling pathways in MDD. Some studies in rodents 84,90 and humans 91 have likewise suggested suppression of microglial immune-response in chronic stress-induced disorders. Furthermore, recent reports provide evidence at gene-expression 9,10,20,75 and protein levels 10,88,92 for a non-inflammatory microglial phenotype in MDD.…”

Section: Discussionmentioning

confidence: 96%

“…MDD-associated downregulation in immune-signaling pathways may be contributed by decreased binding activities of immune-regulatory TFs identified in this study, such as ETS domain and IRFs 34,38 . Likewise, chronic stress-induced depression-like behavior in rodents has been associated with decreased interferon-response TF motif accessibility and transcriptional-repression in microglia 84 . MDD-associated TFs identified in Mic2 were also among those depicting motif accessibility changes in response to disruption in microglia micro-environment and associated with neurodegenerative and psychiatric disorder genes 28 .…”

Section: Discussionmentioning

confidence: 99%

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

Chawla,

Cakmakci,

Zhang

et al. 2023

Preprint

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Major depressive disorder (MDD) associated genetic variants reside primarily in the non-coding, regulatory genome. Here we investigate genome-wide regulatory differences and putative gene-regulatory effects of disease risk-variants by examining chromatin accessibility combined with single-cell gene-expression profiles in over 200,000 cells from the dorsolateral prefrontal cortex (DLPFC) of 84 individuals with MDD and neurotypical controls. MDD-associated accessibility alterations were prominent in deep-layer excitatory neurons characterized by transcription factor (TF) motif accessibility and binding of nuclear receptor (NR)4A2, an activity-dependent TF responsive to pathological stress. The same neurons were significantly enriched for MDD-associated genetic variation disrupting cis-regulatory sites and TF binding associated with genes involved in synaptic communication. Furthermore, a grey matter microglial cluster exhibited differentially closed chromatin in MDD affecting binding sites bound by TFs known to regulate immune homeostasis. In summary, our study points to specific cell types and regulatory mechanisms whereby genetic variation may increase predisposition to MDD.

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“…Analysis was performed as described previously [ 26 ]. In brief, cell clusters were generated with Seurat in the UMAP plot using the published scRNA-seq dataset (GSE60361) [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Chromatin and Transcriptomic Profiling Identifies PU.1 as a Core Regulatory Factor in Microglial Activation Induced by Chronic Cerebral Hypoperfusion

Zhang,

Jin,

Guo

et al. 2023

Mol Neurobiol

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In addition to causing white matter lesions, chronic cerebral hypoperfusion (CCH) can also cause damage to gray matter, but the underlying molecular mechanisms remain largely unknown. In order to obtain a better understanding of the relationship between gene expression and transcriptional regulation alterations, novel upstream regulators could be identified using integration analysis of the transcriptome and epigenetic approaches. Here, a bilateral common carotid artery stenosis (BCAS) model was established for inducing CCH in mice. The spatial cognitive function of mice was evaluated, and changes in cortical microglia morphology were observed. RNA-sequencing (RNA-seq) and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were performed on isolated mouse cortical brain tissue. Then, a systematic joint analysis of BCAS hypoperfusion-induced cortex-specific RNA-seq and ATAC-seq was conducted in order to assess the extent of the correlation between the two, and PU.1 was found to be greatly enriched through motif analysis and transcription factor annotation. Also, the core regulatory factor PU.1 induced by BCAS hypoperfusion was shown to be colocalized with microglia. Based on the above analysis, PU.1 plays a key regulatory role in microglial activation induced by CCH. And the transcriptome and epigenomic data presented in this study can help identify potential targets for future research exploring chronic hypoperfusion-induced brain injury.

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Microglia-specific transcriptional repression of interferon-regulated genes after prolonged stress in mice

Cited by 11 publications

References 76 publications

PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

Differential Chromatin Architecture and Risk Variants in Deep Layer Excitatory Neurons and Grey Matter Microglia Contribute to Major Depressive Disorder

Integrated Analysis of Chromatin and Transcriptomic Profiling Identifies PU.1 as a Core Regulatory Factor in Microglial Activation Induced by Chronic Cerebral Hypoperfusion

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