scholarly journals SCA7 mouse cerebellar pathology reveals preferential downregulation of key Purkinje cell-identity genes and shared disease signature with SCA1 and SCA2.

2020 ◽  
Author(s):  
Anna NIEWIADOMSKA-CIMICKA ◽  
Frédéric Doussau ◽  
Jean-Baptiste Perot ◽  
Michel J Roux ◽  
Céline Keime ◽  
...  
Keyword(s):  
Cell Types ◽  
Spinocerebellar Ataxia Type ◽  
Specific Gene ◽  
Variable Degree ◽  
Saga Complex ◽  
Cell Type ◽  
Motor Incoordination ◽  
Spinocerebellar Ataxia Type 7 ◽  
Cerebellar Cell ◽  
Polyq Expansion

Abstract Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination and visual impairment due to progressive cerebellar and retinal degeneration. Alteration of other nervous tissues also contributes to symptoms. The mechanisms underlying motor incoordination of SCA7 remain to be characterized. SCA7 is caused by a polyglutamine (polyQ) expansion in ATXN7, a member of the transcriptional coactivator SAGA complex, which harbors histone modification activities. PolyQ expansion in other proteins is responsible for 5 other SCAs (SCA1-3, 6 and 17). However, the converging and diverging pathophysiological points remain poorly understood. Using a new SCA7 knock-in model carrying 140 glutamines in ATXN7, we analyzed cell-type specific gene expression in the cerebellum. We show that gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks histone H3 acetylation and H2B ubiquitination. Our results further show that Purkinje cells (PCs) are far the most affected neurons: unlike other cerebellar cell types, PCs show reduced expression of 83 cell-type identity genes, critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC identity genes downregulated in SCA7 mice are also decreased in early symptomatic SCA1 and SCA2 mice, revealing a common signature of early PC pathology involving cGMP-PKG and phosphatidylinositol signaling pathways and long-term depression. Our study thus points out molecular targets for therapeutic development which may prove beneficial for several SCAs. Finally, we show that unlike previous SCA7 mouse models, SCA7140Q/5Q mice exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and vision functions. Therefore, SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.

scholarly journals SCA7 mice recapitulate CNS, PNS and retina pathologies and show a transcriptional signature of Purkinje cell dysfunction prevailing in SCA1 and SCA2 mice.

2020 ◽  
Author(s):  
Anna NIEWIADOMSKA-CIMICKA ◽  
Frédéric Doussau ◽  
Jean-Baptiste Perot ◽  
Michel J Roux ◽  
Céline Keime ◽  
...  
Keyword(s):  
Peripheral Nerves ◽  
Cell Types ◽  
Whole Body ◽  
Spinocerebellar Ataxia Type ◽  
Specific Gene ◽  
Polyglutamine Expansion ◽  
Morphological Alterations ◽  
Transcriptional Signature ◽  
Brain Morphometry ◽  
Spinocerebellar Ataxia Type 7

Abstract Background Background: Spinocerebellar ataxia type 7 (SCA7) is primarily characterized by progressive cerebellar degeneration with major alteration of Purkinje cells (PC) due to polyglutamine expansion in ATXN7, a subunit of SAGA transcriptional co-regulator complex. Additional neural tissues are affected and contribute to diverse symptoms. Current animal models were insufficient to recapitulate the broad spectrum of SCA7 pathology and the mechanisms of PC degeneration remain poorly explored. Methods: To delineate spatio-temporal features of SCA7, we performed a longitudinal characterization of a new knock-in mice line expressing ATXN7 with 140 glutamines (SCA7 140Q/5Q ) using a battery of analyses including motor tests, brain and retina imaging, morphometry, electrophysiology, electron microscopy and immunohistochemistry of disease tissues. We also determined the cerebellar transcriptome and cell-type specific gene deregulation. Results: Here we describe the first SCA7 knock-in mice that combine most cardinal features of SCA7, including retinal, cerebellar, cerebral and peripheral nerves pathologies, which account for progressive impairment of behavior, motor and vision functions. MRI and brain morphometry reveal atrophy of grey and white matter of specific cerebral regions, while peripheral nerves and photoreceptors show functional and morphological alterations. We show that cerebellar pathology is characterized by gene deregulation in all cerebellar cell types and alterations of SAGA-dependent epigenetic marks. Intranuclear accumulation of mutant ATXN7 and gene downregulation precede the onset of PC pacemaker dysfunction. Interestingly, PC show loss of expression of 83 PC-specific genes coding for ion channels, receptors and signaling proteins involved in pacemaker function and long-term depression, which are causal factors of many type of ataxias. Comparison of cerebellar transcriptome with other SCAs reveals a subset of 67 PC-specific genes downregulated in SCA1, SCA2 and SCA7, providing a common signature of early PC dysfunction. Conclusions: The SCA7 140Q/5Q mice represent a promising model for the investigation of different aspects of SCA7 pathogenesis, and offers opportunities for translational development of therapeutic strategies by targeting the brain, retina, peripheral nerve or whole body. Our results also provide insight into converging mechanisms of PC degeneration in polyglutamine SCAs and point out molecular targets for therapeutic development w hich may prove beneficial for several SCAs.

scholarly journals An analytical method for the identification of cell type-specific disease gene modules

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinting Guan ◽  
Yiping Lin ◽  
Yang Wang ◽  
Junchao Gao ◽  
Guoli Ji
Keyword(s):  
Disease Gene ◽  
Gene Interaction ◽  
Cell Types ◽  
Autism Spectrum ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Disease ◽  
Cell Type Specific ◽  
Gene Modules ◽  
Disease Associated Genes

Abstract Background Genome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells. Methods To characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests. Results Between neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules. Conclusions The results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.

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

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ana J. Chucair-Elliott ◽  
Sarah R. Ocañas ◽  
David R. Stanford ◽  
Victor A. Ansere ◽  
Kyla B. Buettner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Affinity Purification ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Tissue Level ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

AbstractEpigenetic regulation of gene expression occurs in a cell type-specific manner. Current cell-type specific neuroepigenetic studies rely on cell sorting methods that can alter cell phenotype and introduce potential confounds. Here we demonstrate and validate a Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) approach for temporally controlled labeling and isolation of ribosomes and nuclei, and thus RNA and DNA, from specific central nervous system cell types. Analysis of gene expression and DNA modifications in astrocytes or microglia from the same animal demonstrates differential usage of DNA methylation and hydroxymethylation in CpG and non-CpG contexts that corresponds to cell type-specific gene expression. Application of this approach in LPS treated mice uncovers microglia-specific transcriptome and epigenome changes in inflammatory pathways that cannot be detected with tissue-level analysis. The NuTRAP model and the validation approaches presented can be applied to any brain cell type for which a cell type-specific cre is available.

scholarly journals Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Natalie M. Clark ◽  
Eli Buckner ◽  
Adam P. Fisher ◽  
Emily C. Nelson ◽  
Thomas T. Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Networks ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Renewal ◽  
Cell Type ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Cell Type Specific ◽  
Stem Cell Type

AbstractStem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred to here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allows us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.

scholarly journals A regulatory element is characterized by purine-mediated and cell-type-specific gene transcription.

1990 ◽  
Vol 10 (8) ◽  
pp. 4356-4364 ◽  
Author(s):  
M J Walsh ◽  
A Sanchez-Pozo ◽  
N S Leleiko
Keyword(s):  
De Novo ◽  
Cell Types ◽  
High Rate ◽  
Specific Gene ◽  
Intestinal Epithelial ◽  
Purine Nucleotide ◽  
Cell Type ◽  
Hprt Gene ◽  
Purine Nucleotides ◽  
Cell Type Specific

Purines and purine nucleotides were found to affect transcription of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in whole nuclei isolated from intestinal mucosa of adult rats fed a purine- and purine nucleotide-free diet. Nuclear run-on transcription assays, performed on whole nuclei from different tissues and cell types, identified an intestine-specific decrease in the overall incorporation of [alpha-32P]UTP in HPRT transcripts from intestinal epithelial cell nuclei when exogenous purines or purine nucleotides were omitted from either the diet or culture medium. Using a 990-base-pair genomic fragment that contains the 5'-flanking region from the HPRT gene, we generated plasmid constructs with deletions, transfected the DNA into various cell types, and assayed for chloramphenicol acetyltransferase (CAT) reporter activity in vitro. We determined that an element upstream from the putative transcriptional start site is necessary to maintain the regulatory response to purine and nucleotide levels in cultured intestinal epithelial cells. These results were tissue and cell type specific and suggest that in the absence of exogenous purines, the presence of specific factors influences transcriptional initiation of HPRT. This information provides evidence for a mechanism by which the intestinal epithelium, which has been reported to lack constitutive levels of de novo purine nucleotide biosynthetic activity, could maintain and regulate the salvage of purines and nucleotides necessary for its high rate of cell and protein turnover during fluctuating nutritional and physiological conditions. Furthermore, this information may provide more insight into regulation of the broad class of genes recognized by their lack of TATA and CCAAT box consensus sequences within the region proximal to the promoter.

scholarly journals Bulk Tissue Cell Type Deconvolution with Multi-Subject Single-Cell Expression Reference

2018 ◽  
Author(s):  
Xuran Wang ◽  
Jihwan Park ◽  
Katalin Susztak ◽  
Nancy R. Zhang ◽  
Mingyao Li
Keyword(s):  
Single Cell ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Tissue Cell ◽  
Specific Gene ◽  
Rna Seq ◽  
Cell Type ◽  
Cell Type Specific ◽  
Cell Expression

AbstractWe present MuSiC, a method that utilizes cell-type specific gene expression from single-cell RNA sequencing (RNA-seq) data to characterize cell type compositions from bulk RNA-seq data in complex tissues. When applied to pancreatic islet and whole kidney expression data in human, mouse, and rats, MuSiC outperformed existing methods, especially for tissues with closely related cell types. MuSiC enables characterization of cellular heterogeneity of complex tissues for identification of disease mechanisms.

scholarly journals Prediction of condition-specific regulatory maps in Arabidopsis using integrated genomic data

2019 ◽  
Author(s):  
Qi Song ◽  
Jiyoung Lee ◽  
Shamima Akter ◽  
Ruth Grene ◽  
Song Li
Keyword(s):  
Stress Responses ◽  
Abiotic Stresses ◽  
Individual Cell ◽  
Genomic Data ◽  
Cell Types ◽  
Root Cell ◽  
Specific Gene ◽  
Open Chromatin ◽  
Cell Type ◽  
Cell Type Specific

AbstractRecent advances in genomic technologies have generated large-scale protein-DNA interaction data and open chromatic regions for multiple plant species. To predict condition specific gene regulatory networks using these data, we developed the Condition Specific Regulatory network inference engine (ConSReg), which combines heterogeneous genomic data using sparse linear model followed by feature selection and stability selection to select key regulatory genes. Using Arabidopsis as a model system, we constructed maps of gene regulation under more than 50 experimental conditions including abiotic stresses, cell type-specific expression, and stress responses in individual cell types. Our results show that ConSReg accurately predicted gene expressions (average auROC of 0.84) across multiple testing datasets. We found that, (1) including open chromatin information from ATAC-seq data significantly improves the performance of ConSReg across all tested datasets; (2) choice of negative training samples and length of promoter regions are two key factors that affect model performance. We applied ConSReg to Arabidopsis single cell RNA-seq data of two root cell types (endodermis and cortex) and identified five regulators in two root cell types. Four out of the five regulators have additional experimental evidence to support their roles in regulating gene expression in Arabidopsis roots. By comparing regulatory maps in abiotic stress responses and cell type-specific experiments, we revealed that transcription factors that regulate tissue levels abiotic stresses tend to also regulate stress responses in individual cell types in plants.

scholarly journals Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology

2021 ◽  
Author(s):  
Amy M. Smith ◽  
Karen Davey ◽  
Stergios Tsartsalis ◽  
Combiz Khozoie ◽  
Nurun Fancy ◽  
...  
Keyword(s):  
Metal Ion ◽  
Ion Homeostasis ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Type ◽  
Transcriptional Responses ◽  
Metal Ion Homeostasis ◽  
Gene Sets ◽  
Alzheimer’S Pathology ◽  
And Control

AbstractTo better define roles that astrocytes and microglia play in Alzheimer’s disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

scholarly journals CT-FOCS: a novel method for inferring cell type-specific enhancer-promoter maps

2019 ◽  
Author(s):  
Tom Aharon Hait ◽  
Ran Elkon ◽  
Ron Shamir
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Expression Patterns ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Type ◽  
Chromatin Interactions ◽  
Cell Type Specific ◽  
Novel Method ◽  
Validation Scheme

AbstractSpatiotemporal gene expression patterns are governed to a large extent by enhancer elements, typically located distally from their target genes. Identification of enhancer-promoter (EP) links that are specific and functional in individual cell types is a key challenge in understanding gene regulation. We introduce CT-FOCS, a new statistical inference method that utilizes multiple replicates per cell type to infer cell type-specific EP links. Computationally predicted EP links are usually benchmarked against experimentally determined chromatin interactions measured by ChIA-PET and promoter-capture HiC techniques. We expand this validation scheme by using also loops that overlap in their anchor sites. In analyzing 1,366 samples from ENCODE, Roadmap epigenomics and FANTOM5, CT-FOCS inferred highly cell type-specific EP links more accurately than state-of-the-art methods. We illustrate how our inferred EP links drive cell type-specific gene expression and regulation.

scholarly journals Genetic, parental and lifestyle factors influence telomere length

2021 ◽  
Author(s):  
Sergio Andreu-Sanchez ◽  
Geraldine Aubert ◽  
Aida Ripoll-Cladellas ◽  
Sandra Henkelman ◽  
Daria V. Zhernakova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Average Length ◽  
Cell Types ◽  
Paternal Age ◽  
Specific Gene ◽  
Cell Type ◽  
Sequencing Data ◽  
Nonsense Mediated Decay ◽  
Cell Type Specific ◽  
Telomere Biology

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1,046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Coupling these measurements to single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.

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