Epigenetics Control Microglia Plasticity

Cheray, Mathilde; Joseph, Bertrand

doi:10.3389/fncel.2018.00243

Cited by 116 publications

(105 citation statements)

References 137 publications

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“…Although a handful of studies have suggested DNA methylation as a principal regulator of microglial activation 34 , little microglia-specific in vivo evidence is available to compare DNA methylation with concurrent changes in transcriptomic response. By coupling LPS administration with the cell type-specific Cx3cr1-NuTRAP model we are able to interrogate dynamic changes in DNA methylation in Cx3cr1 + (microglia) cells with their paired transcriptomic changes indicative of a pro-inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

Chucair-Elliott

Ocañas

Stanford

et al. 2019

Preprint

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23Epigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type 24 specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and 25 introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and 26Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling 27 and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific CNS cell types. 28Paired analysis of the transcriptome and DNA modifications in astrocytes and microglia 29 demonstrates differential usage of DNA methylation and hydroxymethylation in CG and non-CG 30 contexts that corresponds to cell type-specific gene expression. Application of this approach in 31 LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in 32 inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model 33 and the validation approaches presented can be applied to any CNS cell type for which a cell 34 type-specific cre is available. 36Significant advances are being made in understanding the epigenome and its relationship with 37 gene expression in the brain 1-3 . However, the lack of approaches for paired analysis of DNA and 38RNA profiles at the cell type-specific level within the same animal is a significant limitation for the 39 field, given that epigenetic processes differ across CNS cell types at the level of chromatin 40 organization and DNA modifications 1,4 . Obtaining enriched cell populations by flow sorting 41 requires cell surface markers but these markers can change with experimental conditions and cell 42 sorting causes molecular, morphological, and functional changes, such as cell activation, that 43 could confound studies 3,5,6 . Single cell approaches 7 may overcome some of the challenges of 44 cell sorting but the scale of such studies, partial genomic coverage, restriction to only certain types 45 of endpoints, and continued potential for brain dissociation artifacts are limitations. 46This has led to development of transgenic labeling approaches to isolate RNA or DNA from 47 specific cell types. Ribosome labeling and RNA isolation methods, such as Translating Ribosome 48Affinity Purification (TRAP 8 ), and ribosome tagging (RiboTag 9 ), are gaining acceptance across 49 neuroscience studies examining the transcriptome. Similar approaches have been developed to 50 transgenically tag and allow isolation of nuclei and thus DNA (Isolation of Nuclei TAgged in 51 Specific Cell Types, INTACT) 10 . However, using separate transgenic mouse strains for DNA and 52RNA endpoints is a complicated and resource intensive approach. 53Here we describe an approach where Nuclear Tagging and Translating Ribosome Affinity 54Purification (NuTRAP) 11 is combined with well-established cell-specific inducible cre-recombinase 55 expressing systems 12,13 to perform paired transcriptomic and epigenomic analyses of specific 56 CNS cell types in a temporally controllable manner from a single mouse. ...

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Section: Resultsmentioning

confidence: 99%

Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

Chucair-Elliott

Ocañas

Stanford

et al. 2019

Preprint

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“…Neher and coworkers recently demonstrated that peripherally applied inflammatory stimuli which induce either acute immune training (e.g., single intraperitoneal injection of LPS) or tolerance (e.g., daily injections of low‐dose LPS on 4 consecutive days) in the brain lead to differential epigenetic reprogramming, associated with unique transcriptome profiles of microglia that persist for at least half a year (Wendeln et al , ). Epigenetic changes, including histone modifications or DNA methylation as well as microRNA expression, are important modifiers of gene expression, and have been involved in cell phenotype regulation and reprogramming and are therefore part of the mechanisms regulating cellular plasticity including microglia (Cheray & Joseph, ). These two types of immunological imprinting, i.e.…”

Section: Introductionmentioning

confidence: 99%

Microglial subtypes: diversity within the microglial community

et al. 2019

Self Cite

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Microglia are brain‐resident macrophages forming the first active immune barrier in the central nervous system. They fulfill multiple functions across development and adulthood and under disease conditions. Current understanding revolves around microglia acquiring distinct phenotypes upon exposure to extrinsic cues in their environment. However, emerging evidence suggests that microglia display differences in their functions that are not exclusively driven by their milieu, rather by the unique properties these cells possess. This microglial intrinsic heterogeneity has been largely overlooked, favoring the prevailing view that microglia are a single‐cell type endowed with spectacular plasticity, allowing them to acquire multiple phenotypes and thereby fulfill their numerous functions in health and disease. Here, we review the evidence that microglia might form a community of cells in which each member (or “subtype”) displays intrinsic properties and performs unique functions. Distinctive features and functional implications of several microglial subtypes are considered, across contexts of health and disease. Finally, we suggest that microglial subtype categorization shall be based on function and we propose ways for studying them. Hence, we advocate that plasticity (reaction states) and diversity (subtypes) should both be considered when studying the multitasking microglia.

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“…In the group of histone deacetylases (HDAC), expression of several genes was reduced: Hdac4, Hdac5, Hdac8, Hdac9, Hdac11, and Sirt5 ( Figure 3C). We analyzed also expression of genes related to epigenetic regulation, as emerging contributor to microglial plasticity ( Figure 3) [38]. Among tested genes, we focused on those involved in histone acetylation code.…”

Section: Resultsmentioning

confidence: 99%

“…to microglial plasticity ( Figure 3) [38]. Among tested genes, we focused on those involved in histone acetylation code.…”

Section: Resultsmentioning

confidence: 99%

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

Czapski

Zhao

Lukiw

et al. 2020

IJMS

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Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis.

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Epigenetics Control Microglia Plasticity

Cited by 116 publications

References 137 publications

Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

Microglial subtypes: diversity within the microglial community

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

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