scholarly journals NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain

2021 ◽  
Vol 14 ◽  
Author(s):  
Vivek Mahadevan ◽  
Apratim Mitra ◽  
Yajun Zhang ◽  
Xiaoqing Yuan ◽  
Areg Peltekian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Gabaergic Interneuron ◽  
Membrane Excitability ◽  
Risk Genes ◽  
Road Map ◽  
Physiological Properties ◽  
Nmdar Subunit ◽  
Early Developmental

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

scholarly journals NMDAR-mediated transcriptional control of gene expression in the specification of interneuron subtype identity

2020 ◽  
Author(s):  
Vivek Mahadevan ◽  
Apratim Mitra ◽  
Yajun Zhang ◽  
Areg Peltekian ◽  
Ramesh Chittajallu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Medial Ganglionic Eminence ◽  
Membrane Excitability ◽  
Control Of Gene Expression ◽  
Road Map ◽  
Physiological Properties ◽  
Nmdar Subunit

AbstractMedial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+ and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical and physiological properties. However, the molecular mechanisms regulating their diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype identities. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

scholarly journals Molecular Mechanisms, Diagnostic Aspects and Therapeutic Opportunities of Micro Ribonucleic Acids in Atrial Fibrillation

2020 ◽  
Vol 21 (8) ◽  
pp. 2742 ◽  
Author(s):  
Allan Böhm ◽  
Marianna Vachalcova ◽  
Peter Snopek ◽  
Ljuba Bacharova ◽  
Dominika Komarova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Wide Spectrum ◽  
Regulation Of Gene Expression ◽  
Review Article ◽  
Ribonucleic Acids ◽  
Rna Molecules ◽  
Diagnostic Aspects ◽  
Non Coding Rna

Micro ribonucleic acids (miRNAs) are short non-coding RNA molecules responsible for regulation of gene expression. They are involved in many pathophysiological processes of a wide spectrum of diseases. Recent studies showed their involvement in atrial fibrillation. They seem to become potential screening biomarkers for atrial fibrillation and even treatment targets for this arrhythmia. The aim of this review article was to summarize the latest knowledge about miRNA and their molecular relation to the pathophysiology, diagnosis and treatment of atrial fibrillation.

scholarly journals MAP Kinase Pathways in the YeastSaccharomyces cerevisiae

1998 ◽  
Vol 62 (4) ◽  
pp. 1264-1300 ◽  
Author(s):  
Michael C. Gustin ◽  
Jacobus Albertyn ◽  
Matthew Alexander ◽  
Kenneth Davenport
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
Mapk Pathways ◽  
Mapk Cascades

SUMMARY A cascade of three protein kinases known as a mitogen-activated protein kinase (MAPK) cascade is commonly found as part of the signaling pathways in eukaryotic cells. Almost two decades of genetic and biochemical experimentation plus the recently completed DNA sequence of the Saccharomyces cerevisiae genome have revealed just five functionally distinct MAPK cascades in this yeast. Sexual conjugation, cell growth, and adaptation to stress, for example, all require MAPK-mediated cellular responses. A primary function of these cascades appears to be the regulation of gene expression in response to extracellular signals or as part of specific developmental processes. In addition, the MAPK cascades often appear to regulate the cell cycle and vice versa. Despite the success of the gene hunter era in revealing these pathways, there are still many significant gaps in our knowledge of the molecular mechanisms for activation of these cascades and how the cascades regulate cell function. For example, comparison of different yeast signaling pathways reveals a surprising variety of different types of upstream signaling proteins that function to activate a MAPK cascade, yet how the upstream proteins actually activate the cascade remains unclear. We also know that the yeast MAPK pathways regulate each other and interact with other signaling pathways to produce a coordinated pattern of gene expression, but the molecular mechanisms of this cross talk are poorly understood. This review is therefore an attempt to present the current knowledge of MAPK pathways in yeast and some directions for future research in this area.

scholarly journals Comparative Genomics and Transcriptomics To Analyze Fruiting Body Development in Filamentous Ascomycetes

Genetics ◽  
2019 ◽  
Vol 213 (4) ◽  
pp. 1545-1563 ◽  
Author(s):  
Ramona Lütkenhaus ◽  
Stefanie Traeger ◽  
Jan Breuer ◽  
Laia Carreté ◽  
Alan Kuo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fruiting Body ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Comparative Transcriptomics ◽  
Fruiting Bodies ◽  
Body Development ◽  
Fruiting Body Development ◽  
Genes Encoding

Many filamentous ascomycetes develop three-dimensional fruiting bodies for production and dispersal of sexual spores. Fruiting bodies are among the most complex structures differentiated by ascomycetes; however, the molecular mechanisms underlying this process are insufficiently understood. Previous comparative transcriptomics analyses of fruiting body development in different ascomycetes suggested that there might be a core set of genes that are transcriptionally regulated in a similar manner across species. Conserved patterns of gene expression can be indicative of functional relevance, and therefore such a set of genes might constitute promising candidates for functional analyses. In this study, we have sequenced the genome of the Pezizomycete Ascodesmis nigricans, and performed comparative transcriptomics of developing fruiting bodies of this fungus, the Pezizomycete Pyronema confluens, and the Sordariomycete Sordaria macrospora. With only 27 Mb, the A. nigricans genome is the smallest Pezizomycete genome sequenced to date. Comparative transcriptomics indicated that gene expression patterns in developing fruiting bodies of the three species are more similar to each other than to nonsexual hyphae of the same species. An analysis of 83 genes that are upregulated only during fruiting body development in all three species revealed 23 genes encoding proteins with predicted roles in vesicle transport, the endomembrane system, or transport across membranes, and 13 genes encoding proteins with predicted roles in chromatin organization or the regulation of gene expression. Among four genes chosen for functional analysis by deletion in S. macrospora, three were shown to be involved in fruiting body formation, including two predicted chromatin modifier genes.

scholarly journals Hepatic Gene Expression Changes in Hypothyroid Juvenile Mice: Characterization of a Novel Negative Thyroid-Responsive Element

Endocrinology ◽  
2007 ◽  
Vol 148 (8) ◽  
pp. 3932-3940 ◽  
Author(s):  
Hongyan Dong ◽  
Carole L. Yauk ◽  
Andrew Williams ◽  
Alice Lee ◽  
George R. Douglas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Microarrays ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Transient Gene Expression ◽  
Early Response ◽  
Response Element ◽  
Gene Expression Studies ◽  
Maternal Thyroid ◽  
Responsive Element

The molecular mechanisms involved in the response of developing mice to disruptions in maternal thyroid hormone (TH) homeostasis are poorly characterized. We used DNA microarrays to examine a broad spectrum of genes from the livers of mice rendered hypothyroid by treating pregnant mice from gestational d 13 to postnatal d 15 with 6-propyl-2-thiouracil in drinking water. Twenty-four individuals (one male and one female pup from six litters of control or 6-propyl-2-thiouracil treatment groups, respectively) were profiled using Agilent oligonucleotide microarrays. MAANOVA identified 96 differentially expressed genes (false discovery rate adjusted P < 0.1 and fold change > 2 in at least one gender). Of these, 72 genes encode proteins of known function, 15 of which had previously been identified as regulated by TH. Pathway analysis revealed these genes are involved in metabolism, development, cell proliferation, apoptosis, and signal transduction. An immediate-early response gene, Nr4a1 (nuclear receptor subfamily 4, group A, member 1), was up-regulated by 3-fold in hypothyroid juvenile mouse liver; treatment of HepG2 cells with T3 resulted in down-regulation of Nr4a1. A potential thyroid response element −1218 to −1188 bp upstream of the promoter region of Nr4a1 was identified and demonstrated to bind TH receptor (TR)-α and TRβ. Point mutation or deletion of the sequence containing the potential Nr4a1-thyroid response element in transient gene expression studies resulted in both higher basal expression and loss of T3 regulatory capacity, suggesting that this site is responsible for the negative regulation of gene expression by TR and TH.

scholarly journals Molecular signatures of cognition and affect

2020 ◽  
Author(s):  
Justine Y. Hansen ◽  
Ross D. Markello ◽  
Jacob W. Vogel ◽  
Jakob Seidlitz ◽  
Danilo Bzdok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Hierarchical Organization ◽  
Brain Atlas ◽  
Psychological Processes ◽  
Cognitive Architectures ◽  
Neuronal Populations

Regulation of gene expression drives protein interactions that govern synaptic wiring and neuronal activity. The resulting coordinated activity among neuronal populations supports complex psychological processes, yet how gene expression shapes cognition and emotion remains unknown. Here we directly bridge the microscale and macroscale by mapping gene expression patterns to functional activation patterns across the cortical sheet. Applying unsupervised learning to the Allen Human Brain Atlas and Neurosynth databases, we identify a ventromedial-dorsolateral gradient of gene assemblies that separate affective and cognitive domains. This topographic molecular-psychological signature reflects the hierarchical organization of the neocortex, including systematic variations in cell type, myeloarchitecture, laminar differentiation, and intrinsic network affiliation. In addition, this molecular-psychological signature is related to individual differences in cognitive performance, strengthens over neurodevelopment, and can be replicated in two independent repositories. Collectively, our results reveal spatially covarying transcriptomic and cognitive architectures, highlighting the influence that molecular mechanisms exert on psychological processes.

scholarly journals In situ dissection of domain boundaries affect genome topology and gene transcription in Drosophila

2019 ◽  
Author(s):  
Rodrigo G. Arzate-Mejía ◽  
Angel Josué Cerecedo-Castillo ◽  
Georgina Guerrero ◽  
Mayra Furlan-Magaril ◽  
Félix Recillas-Targa
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Topological Defects ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Domain Boundaries ◽  
Topologically Associated Domains ◽  
Genetic Sequences

AbstractThe molecular mechanisms responsible for Topologically Associated Domains (TADs) formation are not yet fully understood. In Drosophila, it has been proposed that transcription is fundamental for TAD organization while the participation of genetic sequences bound by Architectural Proteins (APs) remains controversial. Here, we investigate the contribution of domain boundaries to TAD organization and the regulation of gene expression at the Notch gene locus in Drosophila. We find that deletion of domain boundaries results in TAD fusion and long-range topological defects that are accompanied by loss of APs and RNA Pol II chromatin binding as well as defects in transcription. Together, our results provide compelling evidence on the contribution of discrete genetic sequences bound by APs and RNA Pol II in the partition of the genome into TADs and in the regulation of gene expression in Drosophila.

scholarly journals Cell-type specific cis-eQTLs in eight brain cell-types identifies novel risk genes for human brain disorders

2021 ◽  
Author(s):  
Julien Bryois ◽  
Daniela Calini ◽  
Will Macnair ◽  
Lynette Foo ◽  
Eduard Urich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Risk ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Specific Cell ◽  
Eqtl Analysis ◽  
Cell Type ◽  
Disease Etiology ◽  
Risk Genes ◽  
Cell Type Specific

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous brain tissues as opposed to specific cell types. To investigate the genetics of gene expression in adult human cell types from the central nervous system (CNS), we performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight CNS cell types. We identified 6108 eGenes, a substantial fraction (43%, 2620 out of 6108) of which show cell-type specific effects, with strongest effects in microglia. Integration of CNS cell-type eQTLs with GWAS revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene colocalized in a single cell type providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among CNS cell types and reveal genetic mechanisms by which disease risk genes influence neurological disorders.

scholarly journals  ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

2018 ◽  
Author(s):  
Miguel Hueso ◽  
Josep M Cruzado ◽  
Joan Torras ◽  
Estanis Navarro
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Chaos Theory ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Structural Constraints ◽  
Linear Dynamical Systems ◽  
Alu Elements ◽  
Non Linear ◽  
The Impact

Atherosclerosis (ATH) and Coronary Artery Disease (CAD) are chronic inflammatory diseases with an important genetic background which derive from the cumulative effect of multiple common risk alleles, most of them located in genomic non-coding regions. These complex diseases behave as non-linear dynamical systems that show a high dependence on their initial conditions, so that long-term predictions of disease progression are unreliable. One likely possibility is that the non-linear nature of ATH could be dependent on non-linear correlations in the structure of the human genome. In this review we show how Chaos theory analysis highlighted genomic regions that shared specific structural constraints that could have a role in ATH progression. These regions were shown to be enriched in repetitive sequences of the Alu family, genomic parasites which colonized the human genome, which show a particular secondary structure and have been involved in the regulation of gene expression. We also review the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms by which the Alu elements could alter the inflammatory homeostasis. We devise especial attention to their relationship with the lncRNA ANRIL, the strongest risk factor for ATH, their role as miRNA sponges, and their ability to interfere with the regulatory circuitry of the NF-kB response. We aim to characterize ATH as a non-linear dynamic system in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

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