scholarly journals Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lara Friess ◽  
Mathilde Cheray ◽  
Lily Keane ◽  
Kathleen Grabert ◽  
Bertrand Joseph
Keyword(s):  
Biological Function ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Biological Functions ◽  
Transcriptional Program ◽  
Neuroinflammatory Response ◽  
Transcriptomic Signature ◽  
The Central Nervous System ◽  
Novel Therapeutic Strategies ◽  
Alternative Stimulus

AbstractMicroglia, resident immunocompetent cells of the central nervous system, can display a range of reaction states and thereby exhibit distinct biological functions across development, adulthood and under disease conditions. Distinct gene expression profiles are reported to define each of these microglial reaction states. Hence, the identification of modulators of selective microglial transcriptomic signature, which have the potential to regulate unique microglial function has gained interest. Here, we report the identification of ATG7 (Autophagy-related 7) as a selective modulator of an NF-κB-dependent transcriptional program controlling the pro-inflammatory response of microglia. We also uncover that microglial Atg7-deficiency was associated with reduced microglia-mediated neurotoxicity, and thus a loss of biological function associated with the pro-inflammatory microglial reactive state. Further, we show that Atg7-deficiency in microglia did not impact on their ability to respond to alternative stimulus, such as one driving them towards an anti-inflammatory/tumor supportive phenotype. The identification of distinct regulators, such as Atg7, controlling specific microglial transcriptional programs could lead to developing novel therapeutic strategies aiming to manipulate selected microglial phenotypes, instead of the whole microglial population with is associated with several pitfalls.

scholarly journals Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

2021 ◽  
Vol 288 (1945) ◽  
pp. 20202793
Author(s):  
Alexander Yermanos ◽  
Daniel Neumeier ◽  
Ioana Sandu ◽  
Mariana Borsa ◽  
Ann Cathrin Waindok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
B Cells ◽  
Single Cell ◽  
Somatic Hypermutation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Receptor ◽  
The Central Nervous System

Neuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer's disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system. Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor and T cell receptor repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system of aged male mice. Furthermore, many of these B cells were of the IgM and IgD isotypes, and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.

scholarly journals Identification of Monotonically Differentially Expressed Genes for IFN-β-Treated Multiple Sclerosis Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Suyan Tian ◽  
Lei Zhang
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Biologically Relevant ◽  
Therapeutic Mechanism ◽  
The Central Nervous System ◽  
Multiple Sclerosis Patients ◽  
Term Response

Multiple sclerosis (MS) is a common neurological disability of the central nervous system. Immune-modulatory therapy with interferon-β (IFN-β) has been used as a first-line treatment to prevent relapses in MS patients. While the therapeutic mechanism of IFN-β has not been fully elucidated, the data of microarray experiments that collected longitudinal gene expression profiles to evaluate the long-term response of IFN-β treatment have been analyzed using statistical methods that were incapable of dealing with such data. In this study, the GeneRank method was applied to generate weighted gene expression values and the monotonically expressed genes (MEGs) for both IFN-β treatment responders and nonresponders were identified. The proposed procedure identified 13 MEGs for the responders and 2 MEGs for the nonresponders, most of which are biologically relevant to MS. Our work here provides some useful insight into the mechanism of IFN-β treatment for MS patients. A full understanding of the therapeutic mechanism will enable a more personalized treatment strategy possible.

scholarly journals Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

2020 ◽  
Author(s):  
Alexander Yermanos ◽  
Daniel Neumeier ◽  
Ioana Sandu ◽  
Mariana Borsa ◽  
Ann Cathrin Waindok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
B Cells ◽  
Single Cell ◽  
Somatic Hypermutation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Receptor ◽  
The Central Nervous System

AbstractNeuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer’s disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system (CNS). Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor (BCR) and T cell receptor (TCR) repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system (CNS) of aged mice. Furthermore, many of these B cells were of the IgM and IgD isotype and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.

scholarly journals Profiling microglia from AD donors and non-demented elderly in acute human post-mortem cortical tissue

2020 ◽  
Author(s):  
Astrid M. Alsema ◽  
Qiong Jiang ◽  
Laura Kracht ◽  
Emma Gerrits ◽  
Marissa L. Dubbelaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Post Mortem ◽  
Cortical Tissue ◽  
Risk Genes ◽  
The Central Nervous System ◽  
Neuro Inflammation

AbstractMicroglia are the tissue-resident macrophages of the central nervous system (CNS). Recent studies based on bulk and single-cell RNA sequencing in mice indicate high relevance of microglia with respect to risk genes and neuro-inflammation in Alzheimer’s disease. Here, we investigated microglia transcriptomes at bulk and single cell level in non-demented elderly and AD donors using acute human post-mortem cortical brain samples. We identified 9 human microglial subpopulations with heterogeneity in gene expression. Notably, gene expression profiles and subcluster composition of microglia did not differ between AD donors and non-demented elderly in bulk RNA sequencing nor in single-cell sequencing.

scholarly journals Identification of biomarkers and pathways of mouse embryonic fibroblasts with the dysfunction of mitochondrial DNA

2021 ◽  
Author(s):  
Hanming Gu
Keyword(s):  
Immune Responses ◽  
Metabolic Diseases ◽  
Biological Function ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mitochondrial Diseases ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Multiple Systems ◽  
And Function

Mitochondrial diseases are clinically heterogeneous which involve multiple systems such as organs that are highly dependent on metabolism. Dysfunction of mtDNA is the main cause of mitochondrial diseases that trigger inflammation and immune responses. Here, we aim to identify the biological function and pathways of MEFs with the dysfunction of mtDNA through deletion of YME1L. The gene expression profiles of GSE161735 dataset were originally created by the Illumina NovaSeq 6000 (Mus musculus) for gene biogenesis and function panel. The biological and functional pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), Gene Ontology (GO), and Reactom visual map. KEGG and GO results showed the metabolism and immune responses were mostly affected by the loss of mtDNA. Moreover, we discovered several interacting genes including POLR2F, HIST1H2BJ, PPP1CC, HOXB4, ARG1, APITD1, BUB1B, POLR2K, HOXC4, and HOXB3 were involved in the regulation of metabolic or cancer diseases. Further, we predicted several regulators that had the ability to affect mitochondria during the dysfunction of mtDNA by L1000fwd analysis. Thus, this study provides further insights into the mechanism of mtDNA in metabolic diseases.

scholarly journals Alterations in Chromatin Structure and Function in the Microglia

2021 ◽  
Vol 8 ◽  
Author(s):  
Yuki Fujita ◽  
Toshihide Yamashita
Keyword(s):  
Gene Expression ◽  
Neural Development ◽  
Developmental Stages ◽  
Current Knowledge ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Electrophysiological Properties ◽  
Coordinate Gene Expression ◽  
The Central Nervous System ◽  
And Function

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.

scholarly journals TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2145 ◽  
Author(s):  
Stefano Raffaele ◽  
Marta Lombardi ◽  
Claudia Verderio ◽  
Marta Fumagalli
Keyword(s):  
Extracellular Vesicles ◽  
Cell Communication ◽  
Neuroinflammatory Response ◽  
Brain Functions ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Novel Therapeutic Strategies ◽  
Circuit Formation ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is a pleiotropic cytokine powerfully influencing diverse processes of the central nervous system (CNS) under both physiological and pathological conditions. Here, we analyze current literature describing the molecular processes involved in TNF synthesis and release from microglia, the resident immune cells of the CNS and the main source of this cytokine both in brain development and neurodegenerative diseases. A special attention has been given to the unconventional vesicular pathway of TNF, based on the emerging role of microglia-derived extracellular vesicles (EVs) in the propagation of inflammatory signals and in mediating cell-to-cell communication. Moreover, we describe the contribution of microglial TNF in regulating important CNS functions, including the neuroinflammatory response following brain injury, the neuronal circuit formation and synaptic plasticity, and the processes of myelin damage and repair. Specifically, the available data on the functions mediated by microglial EVs carrying TNF have been scrutinized to gain insights on possible novel therapeutic strategies targeting TNF to foster CNS repair.

Tumor immune landscape of paediatric high-grade gliomas

Brain ◽  
2021 ◽  
Author(s):  
James L Ross ◽  
Jose Velazquez Vega ◽  
Ashley Plant ◽  
Tobey J MacDonald ◽  
Oren J Becher ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
High Grade ◽  
Immune Functions ◽  
Cellular Mechanisms ◽  
Genomic Landscape ◽  
Specific Tumor ◽  
The Central Nervous System ◽  
High Grade Gliomas

Abstract Over the last decade, remarkable progress has been made towards elucidating the origin and genomic landscape of childhood high-grade brain tumors. It has become evident that pediatric high-grade gliomas (pHGGs) differ from adult HGGs with respect to multiple defining aspects including: DNA copy number, gene expression profiles, tumor locations within the central nervous system, and genetic alterations such as somatic histone mutations. Despite these advances, clinical trials for children with glioma have historically been based on ineffective adult regimens that fail to take into consideration the fundamental biological differences between the two. Additionally, although our knowledge of the intrinsic cellular mechanisms driving tumor progression has considerably expanded, little is known concerning the dynamic tumor immune microenvironment (TIME) in pHGGs. In this review, we explore the genetic and epigenetic landscape of pHGGs and how this drives the creation of specific tumor sub-groups with meaningful survival outcomes. Further, we provide a comprehensive analysis of the pHGG TIME and discuss emerging therapeutic efforts aimed at exploiting the immune functions of these tumors.

scholarly journals MicroRNA-124: A Key Player in Microglia-Mediated Inflammation in Neurological Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Jiuhan Zhao ◽  
Zhenwei He ◽  
Jialu Wang
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Biological Functions ◽  
Neuroinflammatory Response ◽  
New Ideas ◽  
The Central Nervous System

Neurological disorders are mainly characterized by progressive neuron loss and neurological deterioration, which cause human disability and death. However, many types of neurological disorders have similar pathological mechanisms, including the neuroinflammatory response. Various microRNAs (miRs), such as miR-21, miR-124, miR-146a, and miR-132 were recently shown to affect a broad spectrum of biological functions in the central nervous system (CNS). Microglia are innate immune cells with important roles in the physiological and pathological activities of the CNS. Recently, abnormal expression of miR-124 was shown to be associated with the occurrence and development of various diseases in CNS via regulating microglia function. In addition, miR-124 is a promising biomarker and therapeutic target. Studies on the role of miR-124 in regulating microglia function involved in pathogenesis of neurological disorders at different stages will provide new ideas for the use of miR-124 as a therapeutic target for different CNS diseases.

scholarly journals Functional contexts of adipose and gluteal muscle tissue gene co-expression networks in the domestic horse

2020 ◽  
Author(s):  
Robert J Schaefer ◽  
Jonah Cullen ◽  
Jane Manfredi ◽  
Molly McCue
Keyword(s):  
Muscle Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Transcriptional Response ◽  
Functional Differentiation ◽  
Biological Functions ◽  
Transcriptional Responses ◽  
Gluteal Muscle ◽  
Gene Sets ◽  
Transcriptional Landscape

Abstract A gene’s response to an environment is tightly bound to the underlying genetic variation present in an individual’s genome and varies greatly depending on the tissue it is being expressed in. Gene co-expression networks provide a mechanism to understand and interpret the collective transcriptional responses of genes. Here, we use the Camoco co-expression network framework to characterize the transcriptional landscape of adipose and gluteal muscle tissue in 83 domestic horses (Equus caballus) representing 5 different breeds. In each tissue, gene expression profiles, capturing transcriptional response due to variation across individuals, were used to build two separate, tissue-focused, genotypically-diverse gene co-expression networks. The aim of our study was to identify significantly co-expressed clusters of genes in each tissue, then compare the clusters across networks to quantify the extent that clusters were found in both networks as well as to identify clusters found in a single network. The known and unknown functions for each network were quantified using complementary, supervised and unsupervised approaches. First, supervised ontological enrichment was utilized to quantify biological functions represented by each network. Curated ontologies (GO and KEGG) were used to measure the known biological functions present in each tissue. Overall, a large percentage of terms (40.3% of GO and 41% of KEGG) were co-expressed in at least one tissue. Many terms were co-expressed in both tissues, however a small proportion of terms exhibited single tissue co-expression suggesting functional differentiation based on curated, functional annotation. To complement this, an unsupervised approach not relying on ontologies was employed. Strongly co-expressed sets of genes defined by Markov clustering identified sets of unannotated genes showing similar patterns of co-expression within a tissue. We compared gene sets across tissues and identified clusters of genes the either segregate in co-expression by tissue or exhibit high levels of co-expression in both tissues. Clusters were also integrated with GO and KEGG ontologies to identify gene sets containing previously curated annotations versus unannotated gene sets indicating potentially novel biological function. Coupling together these transcriptional datasets, we mapped the transcriptional landscape of muscle and adipose setting up a generalizable framework for interpreting gene function for additional tissues in the horse and other species.

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