scholarly journals Alcohol causes lasting differential transcription in Drosophila mushroom body neurons

2019 ◽  
Author(s):  
Emily Petruccelli ◽  
Nicolas Ledru ◽  
Karla R. Kaun
Keyword(s):  
Mushroom Body ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Cell Types ◽  
Memory Encoding ◽  
Sensory Cues ◽  
New Methods ◽  
Specific Regulation ◽  
Context Specific ◽  
Differential Transcription

AbstractRepeated alcohol experiences can produce long-lasting memories for sensory cues associated with intoxication. These memories can ultimately trigger relapse in individuals recovering from alcohol use disorder (AUD). The molecular mechanisms by which alcohol changes memories to become long-lasting and inflexible remain unclear. New methods to analyze gene expression within precise neuronal cell-types can provide further insight towards AUD prevention and treatment. Here, we employed genetic tools in Drosophila melanogaster to investigate the lasting consequences of ethanol on transcription in memory-encoding neurons. Drosophila rely on mushroom body (MB) neurons to make associative memories, including memories of ethanol-associated sensory cues. Differential expression analyses found that distinct transcripts, but not genes, in the MB were associated with experiencing ethanol alone compared to forming a memory of an odor cue associated with ethanol. These findings reveal the dynamic and highly context-specific regulation of splicing associated with encoding behavioral experiences. Our data thus demonstrate that alcohol can have lasting effects on transcription and RNA processing during memory formation, and identify new transcript targets for future AUD and addiction investigation.

scholarly journals Alcohol Causes Lasting Differential Transcription in Drosophila Mushroom Body Neurons

Genetics ◽  
2020 ◽  
Vol 215 (1) ◽  
pp. 103-116
Author(s):  
Emily Petruccelli ◽  
Tariq Brown ◽  
Amanda Waterman ◽  
Nicolas Ledru ◽  
Karla R. Kaun
Keyword(s):  
Mushroom Body ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Cell Types ◽  
Memory Formation ◽  
Regulation Of Transcription ◽  
Sensory Cues ◽  
Specific Regulation ◽  
Context Specific ◽  
Cue Encoding

Repeated alcohol experiences can produce long-lasting memories for sensory cues associated with intoxication. These memories can problematically trigger relapse in individuals recovering from alcohol use disorder (AUD). The molecular mechanisms by which ethanol changes memories to become long-lasting and inflexible remain unclear. New methods to analyze gene expression within precise neuronal cell types can provide further insight toward AUD prevention and treatment. Here, we used genetic tools in Drosophila melanogaster to investigate the lasting consequences of ethanol on transcription in memory-encoding neurons. Drosophila rely on mushroom body (MB) neurons to make associative memories, including memories of ethanol-associated sensory cues. Differential expression analyses revealed that distinct transcripts, but not genes, in the MB were associated with experiencing ethanol alone compared to forming a memory of an odor cue associated with ethanol. Adult MB-specific knockdown of spliceosome-associated proteins demonstrated the necessity of RNA-processing in ethanol memory formation. These findings highlight the dynamic, context-specific regulation of transcription in cue-encoding neurons, and the lasting effect of ethanol on transcript usage during memory formation.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals FMRP has a cell-type-specific role in CA1 pyramidal neurons to regulate autism-related transcripts and circadian memory

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kirsty Sawicka ◽  
Caryn R Hale ◽  
Christopher Y Park ◽  
John J Fak ◽  
Jodi E Gresack ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Rna Binding ◽  
Fragile X ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Cell Type ◽  
Ca1 Pyramidal Neurons ◽  
Mrna Targets ◽  
Specific Regulation

Loss of the RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown how FMRP function varies across brain regions and cell types and how this contributes to disease pathophysiology. Here we use conditional tagging of FMRP and CLIP (FMRP cTag CLIP) to examine FMRP mRNA targets in hippocampal CA1 pyramidal neurons, a critical cell type for learning and memory relevant to FXS phenotypes. Integrating these data with analysis of ribosome-bound transcripts in these neurons revealed CA1-enriched binding of autism-relevant mRNAs, and CA1-specific regulation of transcripts encoding circadian proteins. This contrasted with different targets in cerebellar granule neurons, and was consistent with circadian defects in hippocampus-dependent memory in Fmr1 knockout mice. These findings demonstrate differential FMRP-dependent regulation of mRNAs across neuronal cell types that may contribute to phenotypes such as memory defects and sleep disturbance associated with FXS.

scholarly journals UniPath: A uniform approach for pathway and gene-set based analysis of heterogeneity in single-cell epigenome and transcriptome profiles

2019 ◽  
Author(s):  
Smriti Chawla ◽  
Sudhagar Samydurai ◽  
Say Li Kong ◽  
Zhenxun Wang ◽  
Wai Leong Tam ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Single Cells ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Mouse Cell ◽  
Open Chromatin ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Specific Regulation ◽  
Context Specific

AbstractHere, we introduce UniPath, for representing single-cells using pathway and gene-set enrichment scores by a transformation of their open-chromatin or gene-expression profiles. Besides being robust to variability in dropout, UniPath provides consistency and scalability in estimating gene-set enrichment scores for every cell. UniPath’s approach of predicting temporal-order of single-cells using their gene-set activity score enables suppression of known covariates. UniPath based analysis of mouse cell atlas yielded surprising, albeit biologically-meaningful co-clustering of cell-types from distant organs and helped in annotating many unlabeled cells. By enabling unconventional analysis, UniPath also proves to be useful in inferring context-specific regulation in cancer cells.

scholarly journals The Aryl Hydrocarbon Receptor and the Nervous System

2018 ◽  
Vol 19 (9) ◽  
pp. 2504 ◽  
Author(s):  
Ludmila Juricek ◽  
Xavier Coumoul
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Cell Types ◽  
Dendritic Morphology ◽  
Metabolizing Enzymes ◽  
Common Features ◽  
Aryl Hydrocarbon ◽  
The Common ◽  
Neuronal Proliferation

The aryl hydrocarbon receptor (or AhR) is a cytoplasmic receptor of pollutants. It translocates into the nucleus upon binding to its ligands, and forms a heterodimer with ARNT (AhR nuclear translocator). The heterodimer is a transcription factor, which regulates the transcription of xenobiotic metabolizing enzymes. Expressed in many cells in vertebrates, it is mostly present in neuronal cell types in invertebrates, where it regulates dendritic morphology or feeding behavior. Surprisingly, few investigations have been conducted to unravel the function of the AhR in the central or peripheral nervous systems of vertebrates. In this review, we will present how the AhR regulates neural functions in both invertebrates and vertebrates as deduced mainly from the effects of xenobiotics. We will introduce some of the molecular mechanisms triggered by the well-known AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which impact on neuronal proliferation, differentiation, and survival. Finally, we will point out the common features found in mice that are exposed to pollutants, and in AhR knockout mice.

scholarly journals Single-cell transcriptomes reveal molecular specializations of neuronal cell types in the developing cerebellum

2019 ◽  
Vol 11 (8) ◽  
pp. 636-648 ◽  
Author(s):  
Jian Peng ◽  
Ai-li Sheng ◽  
Qi Xiao ◽  
Libing Shen ◽  
Xiang-Chun Ju ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Granule Cells ◽  
Single Cells ◽  
Expression Patterns ◽  
Neuronal Cell ◽  
Cell Types ◽  
Systematic Investigation ◽  
Secretory Proteins ◽  
Cerebellar Cell

Abstract The cerebellum is critical for controlling motor and non-motor functions via cerebellar circuit that is composed of defined cell types, which approximately account for more than half of neurons in mammals. The molecular mechanisms controlling developmental progression and maturation processes of various cerebellar cell types need systematic investigation. Here, we analyzed transcriptome profiles of 21119 single cells of the postnatal mouse cerebellum and identified eight main cell clusters. Functional annotation of differentially expressed genes revealed trajectory hierarchies of granule cells (GCs) at various states and implied roles of mitochondrion and ATPases in the maturation of Purkinje cells (PCs), the sole output cells of the cerebellar cortex. Furthermore, we analyzed gene expression patterns and co-expression networks of 28 ataxia risk genes, and found that most of them are related with biological process of mitochondrion and around half of them are enriched in PCs. Our results also suggested core transcription factors that are correlated with interneuron differentiation and characteristics for the expression of secretory proteins in glia cells, which may participate in neuronal modulation. Thus, this study presents a systematic landscape of cerebellar gene expression in defined cell types and a general gene expression framework for cerebellar development and dysfunction.

Glia dictate pioneer axon trajectories in the Drosophila embryonic CNS

Development ◽  
2000 ◽  
Vol 127 (2) ◽  
pp. 393-402 ◽  
Author(s):  
A. Hidalgo ◽  
G.E. Booth
Keyword(s):  
Axon Guidance ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Cell Types ◽  
Growth Cones ◽  
Neuronal Cell Bodies ◽  
Direct Formation ◽  
Pioneer Neurons ◽  
Embryonic Cns ◽  
Made In

Whereas considerable progress has been made in understanding the molecular mechanisms of axon guidance across the midline, it is still unclear how the axonal trajectories of longitudinal pioneer neurons, which never cross the midline, are established. Here we show that longitudinal glia of the embryonic Drosophila CNS direct formation of pioneer axon pathways. By ablation and analysis of glial cells missing mutants, we demonstrate that glia are required for two kinds of processes. Firstly, glia are required for growth cone guidance, although this requirement is not absolute. We show that the route of extending growth cones is rich in neuronal cell bodies and glia, and also in long processes from both these cell types. Interactions between neurons, glia and their long processes orient extending growth cones. Secondly, glia direct the fasciculation and defasciculation of axons, which pattern the pioneer pathways. Together these events are essential for the selective fasciculation of follower axons along the longitudinal pathways.

scholarly journals Allosteric regulation of histone lysine methyltransferases: from context-specific regulation to selective drugs

2021 ◽  
Author(s):  
Chen Davidovich ◽  
Qi Zhang
Keyword(s):  
Molecular Mechanisms ◽  
Allosteric Regulation ◽  
Precise Control ◽  
Histone Lysine ◽  
Allosteric Sites ◽  
Lysine Residues ◽  
Lysine Methyltransferases ◽  
Specific Regulation ◽  
Context Specific ◽  
Histone Lysine Methyltransferases

Histone lysine methyltransferases (HKMTs) are key regulators of many cellular processes. By definition, HKMTs catalyse the methylation of lysine residues in histone proteins. The enzymatic activities of HKMTs are under precise control, with their allosteric regulation emerging as a prevalent paradigm. We review the molecular mechanisms of allosteric regulation of HKMTs using well-studied histone H3 (K4, K9, K27 and K36) methyltransferases as examples. We discuss the current advances and future potential in targeting allosteric sites of HKMTs for drug development.

scholarly journals Genetic effects on promoter usage are highly context-specific and contribute to complex traits

2018 ◽  
Author(s):  
Kaur Alasoo ◽  
Julia Rodrigues ◽  
John Danesh ◽  
Daniel F. Freitag ◽  
Dirk S. Paul ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Complex Traits ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Complex Trait ◽  
Transcript Level ◽  
Cell Types ◽  
Inflammatory Stimuli ◽  
Promoter Usage ◽  
Context Specific

AbstractGenetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have now been mapped in multiple cell types and conditions, the molecular mechanisms through which these variants exert their effect have remained elusive. Specifically, changes in transcript usage could arise from promoter choice, alternative splicing or 3′ end choice, but current tuQTL studies have not been able to distinguish between them. Here, we performed comprehensive analysis of RNA-seq data from human macrophages exposed to a range of inflammatory stimuli (IFNγ, Salmonella, IFNγ + Salmonella) and a metabolic stimulus (acetylated LDL), obtained from up to 84 individuals. In addition to conventional gene-level and transcript-level analyses, we also developed an analytical approach to directly quantify promoter, internal exon and 3′ end usage. We found that although naive transcript-level analysis often links single genetic variants to multiple coupled changes on the transcriptome, this appears to be an artefact of incomplete transcript annotations. Most of this coupling disappears when promoters, splicing and 3′ end usage are quantified directly. Furthermore, promoter, splicing and 3′ end QTLs are each enriched in distinct genomic features, suggesting that they are predominantly controlled by independent regulatory mechanisms. We also find that promoter usage QTLs are 50% more likely to be context-specific than canonical splicing QTLs and constitute 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be a previously underappreciated molecular mechanism mediating complex trait associations in a context-specific manner.

scholarly journals Genetic effects on promoter usage are highly context-specific and contribute to complex traits

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kaur Alasoo ◽  
Julia Rodrigues ◽  
John Danesh ◽  
Daniel F Freitag ◽  
Dirk S Paul ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Complex Traits ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Complex Trait ◽  
Transcript Level ◽  
Cell Types ◽  
Multiple Cell ◽  
Promoter Usage ◽  
Context Specific

Genetic variants regulating RNA splicing and transcript usage have been implicated in both common and rare diseases. Although transcript usage quantitative trait loci (tuQTLs) have been mapped across multiple cell types and contexts, it is challenging to distinguish between the main molecular mechanisms controlling transcript usage: promoter choice, splicing and 3ʹ end choice. Here, we analysed RNA-seq data from human macrophages exposed to three inflammatory and one metabolic stimulus. In addition to conventional gene-level and transcript-level analyses, we also directly quantified promoter usage, splicing and 3ʹ end usage. We found that promoters, splicing and 3ʹ ends were predominantly controlled by independent genetic variants enriched in distinct genomic features. Promoter usage QTLs were also 50% more likely to be context-specific than other tuQTLs and constituted 25% of the transcript-level colocalisations with complex traits. Thus, promoter usage might be an underappreciated molecular mechanism mediating complex trait associations in a context-specific manner.

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