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Alterations in Chromatin Structure and Function in the Microglia.

ABSTRACT: Microglia are resident immune cells in the central nervous system (CNS). Microglia exhibit diversity in their morphology, density, electrophysiological properties, and gene expression profiles, and play various roles in neural development and adulthood in both physiological and pathological conditions. Recent transcriptomic analysis using bulk and single-cell RNA-seq has revealed that microglia can shift their gene expression profiles in various contexts, such as developmental stages, aging, and disease progression in the CNS, suggesting that the heterogeneity of microglia may be associated with their distinct functions. Epigenetic changes, including histone modifications and DNA methylation, coordinate gene expression, thereby contributing to the regulation of cellular state. In this review, we summarize the current knowledge regarding the epigenetic mechanisms underlying spatiotemporal and functional diversity of microglia that are altered in response to developmental stages and disease conditions. We also discuss how this knowledge may lead to advances in therapeutic approaches for diseases.

SUBMITTER: Fujita Y

PROVIDER: S-EPMC7858661 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Alterations in Chromatin Structure and Function in the Microglia.

Fujita Yuki Y Yamashita Toshihide T

Frontiers in cell and developmental biology 20210121

Microglia are resident immune cells in the central nervous system (CNS). Microglia exhibit diversity in their morphology, density, electrophysiological properties, and gene expression profiles, and play various roles in neural development and adulthood in both physiological and pathological conditions. Recent transcriptomic analysis using bulk and single-cell RNA-seq has revealed that microglia can shift their gene expression profiles in various contexts, such as developmental stages, aging, and ...[more]

PMID: 33553166

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Project description:BackgroundPoly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated enzyme that participates in processes such as transcription and DNA repair through the regulation of chromatin structure. Accumulating evidence suggests an important role for PARP1 enzymatic activity in promoting CNS inflammation by facilitating the expression of inflammatory cytokines in glial cells. However, the molecular mechanisms by which PARP1 enzymatic activity mediates this process are not well understood. In this report we sought to determine the molecular mechanisms by which PARP1 enzymatic activity facilitates the expression of Il1? and TNF in LPS-stimulated BV2 cells.MethodsPARP1 enzymatic activity and histone ADP-ribosylation were measured in LPS-stimulated BV2 cells by radioactive labelling with (32)P-NAD(+). To assess the effect of histone ADP-ribosylation on nucleosome structure, in vitro nucleosome remodeling, nuclease accessibility and binding assays were performed. These studies were complemented by chromatin immunoprecipitation assays in resting and LPS-stimulated BV2 cells in order to determine the occupancy of PARP1, nucleosomes and the RelA subunit of NF-?B, as well as ADP-ribosylation, at the Il1? and Tnf promoters. Finally, we determined the effect of pharmacological inhibition of PARP1 enzymatic activity on the LPS stimulation-dependent induction of Il1? and Tnf mRNA.ResultsOur results indicate that LPS stimulation induces PARP1 enzymatic activity and histone ADP-ribosylation in the chromatin compartment of BV2 cells. In vitro studies show that nucleosome-bound PARP1 disrupts nucleosome structure histone ADP-ribosylation, increasing the accessibility of nucleosomal DNA. Consistent with this PARP1 is constitutively associated with at the Il1? and Tnf promoters in resting BV2 cells. Upon stimulation with LPS, ADP-ribosylation is observed at these promoters, and this is correlated with increased recruitment of the transcription factor NF-?B, resulting in robust transcription of these inflammatory cytokines. Accordingly, pharmacological inhibition of PARP1 enzymatic activity reduces NF-?B recruitment, and Il1? and Tnf expression in LPS-stimulated microglia.ConclusionsCollectively, our data suggest that PARP1 facilitates inflammatory cytokine expression in microglia by increasing the accessibility of promoter DNA via histone ADP-riboyslation.

Project description:Convergent evidences have revealed that schizophrenia is associated with brain dysconnectivity, which leads to abnormal network organization. However, discrepancies were apparent between the structural connectivity (SC) and functional connectivity (FC) studies, and the relationship between structural and functional deficits in schizophrenia remains largely unknown. In this study, resting-state functional magnetic resonance imaging and structural diffusion tensor imaging were performed in 20 patients with schizophrenia and 20 matched healthy volunteers (patients/controls = 19/17 after head motion rejection). Functional and structural brain networks were obtained for each participant. Graph theoretical approaches were employed to parcellate the FC networks into functional modules. The relationships between the entries of SC and FC were estimated within each module to identify group differences and their correlations with clinical symptoms. Although five common functional modules (including the default mode, occipital, subcortical, frontoparietal, and central modules) were identified in both groups, the patients showed a significantly reduced modularity in comparison with healthy participants. Furthermore, we found that schizophrenia-related aberrations of SC-FC coupling exhibited complex patterns among modules. Compared with controls, patients showed an increased SC-FC coupling in the default mode and the central modules. Moreover, significant SC-FC decoupling was demonstrated in the occipital and the subcortical modules, which was associated with longer duration of illness and more severe clinical manifestations of schizophrenia. Taken together, these findings demonstrated that altered module-dependent SC-FC coupling may underlie abnormal brain function and clinical symptoms observed in schizophrenia and highlighted the potential for using new multimodal neuroimaging biomarkers for diagnosis and severity evaluation of schizophrenia. Hum Brain Mapp 38:2008-2025, 2017. © 2017 Wiley Periodicals, Inc.

Dataset Information

Alterations in Chromatin Structure and Function in the Microglia.

Publications

Alterations in Chromatin Structure and Function in the Microglia.

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