Glioma invasion — Pattern of dissemination by mechanisms of invasion and surgical intervention, pattern of gene expression and its regulatory control by tumorsuppressor p53 and proto-oncogene ETS-1

2003 ◽  
pp. 153-162 ◽  
Author(s):  
A. Giese
Keyword(s):  
Gene Expression ◽  
Surgical Intervention ◽  
Regulatory Control ◽  
Glioma Invasion ◽  
Invasion Pattern

Post-Transcriptional Regulation of Cardiac Sarcomere Protein Titin Through 3’ Untranslated Regions

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Striated Muscle ◽  
Binding Capacity ◽  
Structural Features ◽  
Neonatal Rat ◽  
Regulatory Control ◽  
Untranslated Regions ◽  
Luciferase Reporter ◽  
Regulatory Effects

Titin is the largest known protein in the human body, and forms the backbone of all striated muscle sarcomeres. The elastic nature of titin is an important component of muscle compliance and functionality. A significant amount of energy is expended to synthesize titin, thus we postulate that titin gene expression is under strict regulatory control in order to conserve cellular resources. In general, gene expression is mediated in part by post-transcriptional control elements located within the 5’ and 3’ untranslated regions (UTRs) of mature mRNA. The 3’UTR in particular contains structural features that affect binding capacity to other RNA components, such as MicroRNA, which control mRNA localization, translation, and degradation. The degree and significance of the regulatory effects mediated by two determined variants of titin’s 3’ UTR were evaluated in Neonatal Rat Ventricular Myocyte and Human Embryonic Kidney cell lines. Recombinant plasmids to transfect these cells lines were engineered by insertion of the variant titin 3’UTR 431- and 1047-base pairs sequences into luciferase reporter vectors. Expression due to an unaltered reporter vector served as the control. Quantitative changes in luciferase activity due to the recombinants proportionally represented the effect titin’s respective 3’UTR conferred on downstream post-transcriptional expression relative to the control. The effect due to titin’s shorter 3’UTR sequence was inconclusive; however, results illustrated that titin’s longer 3’UTR sequence caused a 35 percent decrease in protein expression. Secondary structural analysis of the two sequences revealed differential folding patterns that affect the stability and degree of MicroRNA-binding within titin’s variant 3’UTR sequences.

scholarly journals Epigenomic and Transcriptomic Dynamics During Human Heart Organogenesis

2020 ◽  
Vol 127 (9) ◽  
Author(s):  
Jennifer VanOudenhove ◽  
Tara N. Yankee ◽  
Andrea Wilderman ◽  
Justin Cotney
Keyword(s):  
Gene Expression ◽  
Congenital Heart Defects ◽  
Human Heart ◽  
Congenital Heart ◽  
Heart Defects ◽  
Regulatory Control ◽  
Whole Genome Sequencing Data ◽  
Regulatory Sequences ◽  
Sequencing Data ◽  
Number Of Patients

Rationale: There is growing evidence that common variants and rare sequence alterations in regulatory sequences can result in birth defects or predisposition to disease. Congenital heart defects are the most common birth defect and have a clear genetic component, yet only a third of cases can be attributed to structural variation in the genome or a mutation in a gene. The remaining unknown cases could be caused by alterations in regulatory sequences. Objective: Identify regulatory sequences and gene expression networks that are active during organogenesis of the human heart. Determine whether these sites and networks are enriched for disease-relevant genes and associated genetic variation. Methods and Results: We characterized ChromHMM (chromatin state) and gene expression dynamics during human heart organogenesis. We profiled 7 histone modifications in embryonic hearts from each of 9 distinct Carnegie stages (13–14, 16–21, and 23), annotated chromatin states, and compared these maps to over 100 human tissues and cell types. We also generated RNA-sequencing data, performed differential expression, and constructed weighted gene coexpression networks. We identified 177 412 heart enhancers; 12 395 had not been previously annotated as strong enhancers. We identified 92% of all functionally validated heart-positive enhancers (n=281; 7.5× enrichment; P <2.2×10 −16 ). Integration of these data demonstrated novel heart enhancers are enriched near genes expressed more strongly in cardiac tissue and are enriched for variants associated with ECG measures and atrial fibrillation. Our gene expression network analysis identified gene modules strongly enriched for heart-related functions, regulatory control by heart-specific enhancers, and putative disease genes. Conclusions: Well-connected hub genes with heart-specific expression targeted by embryonic heart-specific enhancers are likely disease candidates. Our functional annotations will allow for better interpretation of whole genome sequencing data in the large number of patients affected by congenital heart defects.

scholarly journals An Archaeal Fluoride-Responsive Riboswitch Provides an Inducible Expression System for Hyperthermophiles

2018 ◽  
Vol 84 (7) ◽  
Author(s):  
Michael Clayton Speed ◽  
Brett W. Burkhart ◽  
Jonathan W. Picking ◽  
Thomas J. Santangelo
Keyword(s):  
Gene Expression ◽  
Transcription Initiation ◽  
Expression System ◽  
Regulatory Control ◽  
Cell Physiology ◽  
Content Type ◽  
Thermococcus Kodakarensis ◽  
Export Pathway ◽  
Regulated Expression ◽  
Regulated Gene Expression

ABSTRACT Robust genetic systems for the hyperthermophilic Thermococcales have facilitated the overexpression of native genes, enabled the addition of sequences encoding secretion signals, epitope, and affinity tags to coding regions, and aided the introduction of sequences encoding new proteins in these fast-growing fermentative heterotrophs. However, tightly controlled and easily manipulated systems facilitating regulated gene expression are limited for these hosts. Here, we describe an alternative method for regulatory control reliant on a cis -encoded functional riboswitch in the model archaeon Thermococcus kodakarensis . Despite the hyperthermophilic growth temperatures, the proposed structure of the riboswitch conforms to a fluoride-responsive riboswitch encoded in many bacteria and similarly functions to regulate a component-conserved fluoride export pathway. Deleting components of the fluoride export pathway generates T. kodakarensis strains with increased fluoride sensitivity. The mechanism underlying regulated expression suggested that the riboswitch-encoding sequences could be utilized as a tunable expression cassette. When appended to a reporter gene, the riboswitch-mediated control system provides fluoride-dependent tunable regulatory potential, offering an alternative system for regulating gene expression. Riboswitch-regulated expression is thus ubiquitous in extant life and can be exploited to generate regulated expression systems for hyperthermophiles. IMPORTANCE Gene expression is controlled by a myriad of interconnected mechanisms that interpret metabolic states and environmental cues to balance cell physiology. Transcription regulation in Archaea is known to employ both typical repressors-operators and transcription activators to regulate transcription initiation in addition to the regulation afforded by chromatin structure. It was perhaps surprising that the presumed ancient mechanism of riboswitch-mediated regulation is found in Bacteria and Eukarya , but seemingly absent in Archaea . We demonstrate here that a fluoride-responsive riboswitch functions to regulate a detoxification pathway in the hyperthermophilic archaeon Thermococcus kodakarensis . The results obtained define a universal role for riboswitch-mediated regulation, adumbrate the presence of several riboswitch-regulated genes in Thermococcus kodakarensis , demonstrate the utility of RNA-based regulation at high temperatures, and provide a novel riboswitch-regulated expression system to employ in hyperthermophiles.

scholarly journals Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Genes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 19 ◽  
Author(s):  
Harmen Hawer ◽  
Alexander Hammermeister ◽  
Keerthiraju Ravichandran ◽  
Sebastian Glatt ◽  
Raffael Schaffrath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Disease ◽  
Messenger Rna ◽  
Environmental Changes ◽  
Mrna Translation ◽  
Regulatory Control ◽  
Trna Modification ◽  
Positive Role ◽  
Trna Modifications

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

scholarly journals Attenuation of Glucocorticoid Signaling through Targeted Degradation of p300 via the 26S Proteasome Pathway

2002 ◽  
Vol 16 (12) ◽  
pp. 2819-2827 ◽  
Author(s):  
Qiao Li ◽  
Anna Su ◽  
Jihong Chen ◽  
Yvonne A. Lefebvre ◽  
Robert J. G. Haché
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Sodium Butyrate ◽  
Steroid Receptor ◽  
26S Proteasome ◽  
Regulatory Control ◽  
Specific Gene ◽  
Control Of Gene Expression ◽  
Steroid Receptor Coactivator ◽  
Proteasome Pathway

Abstract The effects of acetylation on gene expression are complex, with changes in chromatin accessibility intermingled with direct effects on transcriptional regulators. For the nuclear receptors, both positive and negative effects of acetylation on specific gene transcription have been observed. We report that p300 and steroid receptor coactivator 1 interact transiently with the glucocorticoid receptor and that the acetyltransferase activity of p300 makes an important contribution to glucocorticoid receptor-mediated transcription. Treatment of cells with the deacetylase inhibitor, sodium butyrate, inhibited steroid-induced transcription and altered the transient association of glucocorticoid receptor with p300 and steroid receptor coactivator 1. Additionally, sustained sodium butyrate treatment induced the degradation of p300 through the 26S proteasome pathway. Treatment with the proteasome inhibitor MG132 restored both the level of p300 protein and the transcriptional response to steroid over 20 h of treatment. These results reveal new levels for the regulatory control of gene expression by acetylation and suggest feedback control on p300 activity.

scholarly journals Global transcriptional response of Methylorubrum extorquens to formaldehyde stress expands the role of EfgA and is distinct from antibiotic translational inhibition

2021 ◽  
Author(s):  
Jannell Bazurto ◽  
Siavash Riazi ◽  
Simon D'Alton ◽  
Daniel E. Deatherage ◽  
Eric L. Bruger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carbon Source ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Biological Molecules ◽  
Regulatory Control ◽  
Translation Inhibition ◽  
Translational Inhibition ◽  
Potential Carbon

The potency and indiscriminate nature of formaldehyde reactivity upon biological molecules make it a universal stressor. However, some organisms such as Methylorubrum extorquens possess means to rapidly and effectively mitigate formaldehyde-induced damage. EfgA is a recently identified formaldehyde sensor predicted to halt translation in response to elevated formaldehyde as a means to protect cells. Herein, we investigate growth and changes in gene expression to understand how M. extorquens responds to formaldehyde with and without the EfgA-formaldehyde-mediated translational response, and how this mechanism compares to antibiotic-mediated translation inhibition. These distinct mechanisms of translation inhibition have notable differences: they each involve different specific players and in addition, formaldehyde also acts as a general, multi-target stressor and a potential carbon source. We present findings demonstrating that in addition to its characterized impact on translation, functional EfgA allows for a rapid and robust transcriptional response to formaldehyde and that removal of EfgA leads to heightened proteotoxic and genotoxic stress in the presence of increased formaldehyde levels. We also found that many downstream consequences of translation inhibition were shared by EfgA-formaldehyde- and kanamycin-mediated translation inhibition. Our work uncovered additional layers of regulatory control enacted by functional EfgA upon experiencing formaldehyde stress, and further demonstrated the importance this protein plays at both transcriptional and translational levels in this model methylotroph.

scholarly journals Comparative chromatin accessibility upon BDNF-induced neuronal activity delineates neuronal regulatory elements

2021 ◽  
Author(s):  
Ignacio L. Ibarra ◽  
Vikram S. Ratnu ◽  
Lucia Gordillo ◽  
In-Young Hwang ◽  
Luca Mariani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
Cortical Neurons ◽  
Complex Traits ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Control ◽  
Comparative Genomic ◽  
Regulatory Sequences

Neuronal activity induced by brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences decreased BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal activity.

scholarly journals Longitudinal network theory approaches identify crucial factors affecting sporulation efficiency in yeast

2016 ◽  
Author(s):  
Camellia Sarkar ◽  
Saumya Gupta ◽  
Rahul Kumar Verma ◽  
Himanshu Sinha ◽  
Sarika Jalan
Keyword(s):  
Gene Expression ◽  
Network Theory ◽  
Phenotypic Diversity ◽  
Natural Populations ◽  
Clustering Coefficient ◽  
Regulatory Control ◽  
Global Network ◽  
Node Degree ◽  
Developmental Processes ◽  
Network Properties

ABSTRACTIntegrating network theory approaches over longitudinal genome-wide gene expression data is a robust approach to understand the molecular underpinnings of a dynamic biological process. Here, we performed a network-based investigation of longitudinal gene expression changes during sporulation of a yeast strain, SK1. Using global network attributes, viz. clustering coefficient, degree distribution of a node, degree-degree mixing of the connected nodes and disassortativity, we observed dynamic changes in these parameters indicating a highly connected network with inter-module crosstalk. Analysis of local attributes, such as clustering coefficient, hierarchy, betweenness centrality and Granovetter’s weak ties showed that there was an inherent hierarchy under regulatory control that was determined by specific nodes. Biological annotation of these nodes indicated the role of specifically linked pairs of genes in meiosis. These genes act as crucial regulators of sporulation in the highly sporulating SK1 strain. An independent analysis of these network properties in a less efficient sporulating strain helped to understand the heterogeneity of network profiles. We show that comparison of network properties has the potential to identify candidate nodes contributing to the phenotypic diversity of developmental processes in natural populations. Therefore, studying these network parameters as described in this work for dynamic developmental processes, such as sporulation in yeast and eventually in disease progression in humans, can help in identifying candidate factors which are potential regulators of differences between normal and perturbed processes and can be causal targets for intervention.

Ligand-dependent regulation of NPR-A gene expression in inner medullary collecting duct cells

1998 ◽  
Vol 275 (1) ◽  
pp. F119-F125 ◽  
Author(s):  
Li Cao ◽  
Song Cang Chen ◽  
Tong Cheng ◽  
Michael H. Humphreys ◽  
David G. Gardner
Keyword(s):  
Gene Expression ◽  
Natriuretic Peptide ◽  
Cell Population ◽  
Promoter Activity ◽  
Collecting Duct ◽  
Receptor Activity ◽  
Regulatory Control ◽  
Mrna Levels ◽  
Inner Medullary Collecting Duct ◽  
Medullary Collecting Duct

Atrial natriuretic peptide (ANP) interacts with high-affinity, guanylyl cyclase-linked receptors in the inner medullary collecting duct (IMCD), where it exerts important regulatory control over sodium handling. We sought to determine whether receptor activity in these cells would be modulated (downregulated) by prolonged exposure to ligand. A number of natriuretic peptides (ANP, brain natriuretic peptide, and urodilatin) were found to decrease ligand-dependent natriuretic peptide receptor A (NPR-A) activity in IMCD cells. This inhibition was in direct proportion to their capacity to increase basal cGMP levels in this cell population. The reduction in receptor activity was accompanied by a dose- and time-dependent reduction in NPR-A mRNA levels in these cells. The decrease in transcript levels arose, in part, from a reduction in NPR-A gene transcription. ANP reduced NPR-A gene promoter activity in a transiently transfected IMCD cell population. 8-Bromo-cGMP was also effective in inhibiting NPR-A mRNA levels and NPR-A promoter activity, suggesting that the second messenger (i.e., cGMP) rather than ANP, itself, is responsible for downregulation of NPR-A gene expression.

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