scholarly journals Small transcriptional differences lead to distinct NF-κB dynamics in quasi-identical cells

2021 ◽  
Author(s):  
Cise Kizilirmak ◽  
Emanuele Monteleone ◽  
Jose M. Garcia-Manteiga ◽  
Francesca Brambilla ◽  
Alessandra Agresti ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Nuclear Factor Κb ◽  
Dynamic Responses ◽  
Fine Tuning ◽  
General Mechanism ◽  
Produce Cell ◽  
Regulatory Circuit ◽  
Expression Of Genes ◽  
Inflammatory Stimuli ◽  
Transcriptomics Data

Transcription factor dynamics is fundamental to determine the activation of accurate transcriptional programs and yet is heterogeneous at single-cell level. The source of this dynamic variability is not completely understood. Here we focus on the nuclear factor κB (NF-κB), whose dynamics have been reported to cover a wide spectrum ranging from oscillatory to non-oscillatory. We show that clonal populations of immortalized fibroblasts derived from a single mouse embryo (that can hence be considered quasi-identical) display robustly distinct dynamics upon tumor necrosis α (TNF-α) stimulation. Combining transcriptomics, data-constrained mathematical modelling, and mRNA interference we show that small differences in the expression of genes belonging to the NF-κB regulatory circuit are predictive of the distinct responses to inflammatory stimuli observed among the clones. We propose that this transcriptional fine-tuning can be a general mechanism to produce cell subpopulations with distinct dynamic responses to stimuli within homogeneous cell populations.

scholarly journals A transcriptional regulatory circuit for the photosynthetic acclimation of microalgae to carbon dioxide limitation

2020 ◽  
Author(s):  
Olga Blifernez-Klassen ◽  
Hanna Berger ◽  
Birgit Gerlinde Katharina Mittmann ◽  
Viktor Klassen ◽  
Louise Schelletter ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Protein Interactions ◽  
Prolonged Exposure ◽  
Light Harvesting ◽  
Low Carbon ◽  
Protein Protein Interactions ◽  
Regulatory Circuit ◽  
Expression Of Genes ◽  
Transcriptional Regulatory ◽  
Squamosa Promoter Binding Protein

ABSTRACTIn green microalgae, prolonged exposure to inorganic carbon depletion requires long-term acclimation responses, based on a modulated expression of genes and adjusting photosynthetic activity to the prevailing supply of carbon dioxide. Here, we depict a microalgal regulatory cycle, adjusting the light-harvesting capacity at PSII to the prevailing supply of carbon dioxide in Chlamydomonas reinhardtii. It engages a newly identified low carbon dioxide response factor (LCRF), which belongs to the Squamosa promoter binding protein (SBP) family of transcription factors, and the previously characterized cytosolic translation repressor NAB1. LCRF combines a DNA-binding SBP domain with a conserved domain for protein-protein interactions and transcription of the LCRF gene is rapidly induced by carbon dioxide depletion. LCRF activates transcription of the NAB1 gene by specifically binding to tetranucleotide motifs present in its promoter. Accumulation of the NAB1 protein enhances translational repression of its prime target mRNA, encoding the PSII-associated major light-harvesting protein LHCBM6. The resulting reduction of the PSII antenna size helps maintaining a low excitation during the prevailing carbon dioxide limitation. Analyses of low carbon dioxide acclimation in nuclear insertion mutants devoid of a functional LCRF gene confirm the essentiality of this novel transcription factor for the regulatory circuit.

Methylation of the nuclear poly(A)-binding protein by type I protein arginine methyltransferases – how and why

2013 ◽  
Vol 394 (8) ◽  
pp. 1029-1043 ◽  
Author(s):  
Elmar Wahle ◽  
Bodo Moritz
Keyword(s):  
Active Sites ◽  
Binding Protein ◽  
Arginine Methylation ◽  
Fine Tuning ◽  
General Mechanism ◽  
Type I ◽  
Protein Arginine Methyltransferases ◽  
Low Protein ◽  
Backbone Conformation ◽  
Arginine Residues

Abstract Asymmetric dimethylation of arginine side chains in proteins is a frequent posttranslational modification, catalyzed by type I protein arginine methyltransferases (PRMTs). This article summarizes what is known about this modification in the nuclear poly(A)-binding protein (PABPN1). PABPN1 contains 13 dimethylated arginine residues in its C-terminal domain. Three enzymes, PRMT1, 3, and 6, can methylate PABPN1. Although 26 methyl groups are transferred to one PABPN1 molecule, the PRMTs do so in a distributive reaction, i.e., only a single methyl group is transferred per binding event. As PRMTs form dimers, with the active sites accessible from a small central cavity, backbone conformation around the methyl-accepting arginine is an important determinant of substrate specificity. Neither the association of PABPN1 with poly(A) nor its role in poly(A) tail synthesis is affected by arginine methylation. At least at low protein concentration, methylation does not affect the protein’s tendency to oligomerize. The dimethylarginine residues of PABPN1 are located in the binding site for its nuclear import receptor, transportin. Arginine methylation weakens this interaction about 10-fold. Very recent evidence suggests that arginine methylation as a way of fine-tuning the interactions between transportin and its cargo may be a general mechanism.

scholarly journals Cyclophilin a as a Mediator of Tissue Injure and Nephrotoxicity

2012 ◽  
Vol 4 (2) ◽  
pp. 42-44
Author(s):  
Grace Moscoso-Solorzano ◽  
Gianna Mastroianni-Kirsztajn
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Cyclophilin A ◽  
Common Mechanism ◽  
Ppiase Activity ◽  
Expression Of Genes ◽  
Inflammatory Stimuli ◽  
Genes Encoding ◽  
Inflammatory Processes

Cyclophilin A (CypA) belongs to the peptidyl-prolil isomerase (PPlase) family of proteins and it is also known as the cellular receptor for cyclosporine A (CsA). CsA binds to CypA and inhibits the PPIase activity, but the CypA-CsA complex also binds to calcineurin that promotes the expression of genes encoding cytokines and other proteins required for immune response. In addition, the polymorphism variation of CypA promoter seems to have an influence on the expression of CypA in in vitro studies. CypA was also implicated in inflammatory processes (such as, among others, those observed in rheumatoid arthritis, atherosclerotic disease, nephrotoxicity) and it can be secreted by cells in response to inflammatory stimuli. CypA can also have a role in the molecular mechanisms by which CsA induces nephroxicity but these remain poorly understood. Recent studies suggest that CsA inhibition of CypA PPlase activity is a possible mechanism of this drug toxicity. In addition, CypA overexpression could be protective against CsA nephrotoxicity. Finally, the putative common mechanism by which CypA could be involved in CsA nephrotoxicity and tissue injury is related to its proinflammatory effects in cells.

scholarly journals Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1677
Author(s):  
Håkon Reikvam
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Metabolic Regulation ◽  
Leukemia Cell ◽  
Gene Mutations ◽  
Nuclear Factor Κb ◽  
Myelogenous Leukemia ◽  
Nucleic Acid Binding ◽  
Gene Expressions ◽  
Expression Of Genes ◽  
Acute Myelogenous

Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.

scholarly journals Sexual Differentiation Is Coordinately Regulated by Cryptococcus neoformans CRK1 and GAT1

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 669
Author(s):  
Kuang-Hung Liu ◽  
Wei-Chiang Shen
Keyword(s):  
Cryptococcus Neoformans ◽  
Sexual Differentiation ◽  
Regulatory Networks ◽  
Genetic Interaction ◽  
Negative Regulator ◽  
Wild Type ◽  
Basidiomycetous Fungus ◽  
Regulatory Circuit ◽  
Expression Of Genes ◽  
In The Wild

The heterothallic basidiomycetous fungus Cryptococcus neoformans has two mating types, MATa and MATα. Morphological progression of bisexual reproduction in C. neoformans is as follows: yeast to hyphal transition, filament extension, basidium formation, meiosis, and sporulation. C. neoformans Cdk-related kinase 1 (CRK1) is a negative regulator of bisexual mating. In this study, we characterized the morphological features of mating structures in the crk1 mutant and determined the genetic interaction of CRK1 in the regulatory networks of sexual differentiation. In the bilateral crk1 mutant cross, despite shorter length of filaments than in the wild-type cross, dikaryotic filaments and other structures still remained intact during bisexual mating, but the timing of basidium formation was approximately 18 h earlier than in the cross between wild type strains. Furthermore, gene expression analyses revealed that CRK1 modulated the expression of genes involved in the progression of hyphal elongation, basidium formation, karyogamy and meiosis. Phenotypic results showed that, although deletion of C. neoformans CRK1 gene increased the efficiency of bisexual mating, filamentation in the crk1 mutant was blocked by MAT2 or ZNF2 mutation. A bioinformatics survey predicted the C. neoformans GATA transcriptional factor Gat1 as a potential substrate of Crk1 kinase. Our genetic and phenotypic findings revealed that C. neoformans GAT1 and CRK1 formed a regulatory circuit to negatively regulate MAT2 to control filamentation progression and transition during bisexual mating.

scholarly journals Fine-tuning nucleophosmin in macrophage differentiation and activation

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4694-4704 ◽  
Author(s):  
Leslie Guery ◽  
Naïma Benikhlef ◽  
Thomas Gautier ◽  
Catherine Paul ◽  
Gaetan Jego ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Gene Promoter ◽  
Full Length ◽  
Fine Tuning ◽  
Dual Function ◽  
Macrophage Phenotype ◽  
Blood Monocytes ◽  
Inflammatory Cytokine Production ◽  
Inflammatory Stimuli ◽  
Genes Encoding

Abstract M-CSF–driven differentiation of peripheral blood monocytes is one of the sources of tissue macrophages. In humans and mice, the differentiation process involves the activation of caspases that cleave a limited number of proteins. One of these proteins is nucleophosmin (NPM1), a multifunctional and ubiquitous protein. Here, we show that caspases activated in monocytes exposed to M-CSF cleave NPM1 at D213 to generate a 30-kDa N-terminal fragment. The protein is further cleaved into a 20-kDa fragment, which involves cathepsin B. NPM1 fragments contribute to the limited motility, migration, and phagocytosis capabilities of resting macrophages. Their activation with lipopolysaccharides inhibits proteolytic processes and restores expression of the full-length protein that negatively regulates the transcription of genes encoding inflammatory cytokines (eg, NPM1 is recruited with NF-κB on the MCP1 gene promoter to decrease its transcription). In mice with heterozygous npm gene deletion, cytokine production in response to lipopolysaccharides, including CXCL1 (KC), MCP1, and MIP2, is dramatically enhanced. These results indicate a dual function of NPM1 in M-CSF–differentiated macrophages. Proteolysis of the protein participates in the establishment of a mature macrophage phenotype. In response to inflammatory stimuli, the full-length protein negatively regulates inflammatory cytokine production.

scholarly journals Adaptation of Bacillus subtilis to growth at low temperature: a combined transcriptomic and proteomic appraisal

Microbiology ◽  
2006 ◽  
Vol 152 (3) ◽  
pp. 831-853 ◽  
Author(s):  
Ina Budde ◽  
Leif Steil ◽  
Christian Scharf ◽  
Uwe Völker ◽  
Erhard Bremer
Keyword(s):  
Bacillus Subtilis ◽  
Low Temperature ◽  
Response Regulator ◽  
Proteome Analysis ◽  
Atp Synthesis ◽  
Fine Tuning ◽  
Transcriptional Responses ◽  
Natural Habitats ◽  
Regulatory Circuit ◽  
Proteomic Approach

The soil bacterium Bacillus subtilis frequently encounters a reduction in temperature in its natural habitats. Here, a combined transcriptomic and proteomic approach has been used to analyse the adaptational responses of B. subtilis to low temperature. Propagation of B. subtilis in minimal medium at 15 °C triggered the induction of 279 genes and the repression of 301 genes in comparison to cells grown at 37 °C. The analysis thus revealed profound adjustments in the overall gene expression profile in chill-adapted cells. Important transcriptional changes in low-temperature-grown cells comprise the induction of the SigB-controlled general stress regulon, the induction of parts of the early sporulation regulons (SigF, SigE and SigG) and the induction of a regulatory circuit (RapA/PhrA and Opp) that is involved in the fine-tuning of the phosphorylation status of the Spo0A response regulator. The analysis of chill-stress-repressed genes revealed reductions in major catabolic (glycolysis, oxidative phosphorylation, ATP synthesis) and anabolic routes (biosynthesis of purines, pyrimidines, haem and fatty acids) that likely reflect the slower growth rates at low temperature. Low-temperature repression of part of the SigW regulon and of many genes with predicted functions in chemotaxis and motility was also noted. The proteome analysis of chill-adapted cells indicates a major contribution of post-transcriptional regulation phenomena in adaptation to low temperature. Comparative analysis of the previously reported transcriptional responses of cold-shocked B. subtilis cells with this data revealed that cold shock and growth in the cold constitute physiologically distinct phases of the adaptation of B. subtilis to low temperature.

scholarly journals Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea

2014 ◽  
Vol 197 (3) ◽  
pp. 451-458 ◽  
Author(s):  
Semen A. Leyn ◽  
Dmitry A. Rodionov
Keyword(s):  
Comparative Genomics ◽  
Binding Sites ◽  
Metal Uptake ◽  
Metal Homeostasis ◽  
Content Type ◽  
Expression Of Genes ◽  
Dna Binding Sites ◽  
Palindromic Structure ◽  
Transcriptomics Data ◽  
Uptake Transporters

The DtxR family consists of metal-dependent transcription factors (DtxR-TFs) that regulate the expression of genes involved in metal homeostasis in the cell. The majority of characterized DtxR-TFs belong toBacteria. In the current work, we applied a comparative genomics approach to predict DNA-binding sites and reconstruct regulons for DtxR-TFs inArchaea. As a result, we inferred 575 candidate binding sites for 139 DtxR-TFs in 77 genomes from 15 taxonomic orders. Novel DNA motifs of archaeal DtxR-TFs that have a common palindromic structure were classified into 10 distinct groups. By combining functional regulon reconstructions with phylogenetic analysis, we selected 28 DtxR-TF clades and assigned them metal specificities and regulator names. The reconstructed FetR (ferrous iron), MntR (manganese), and ZntR (zinc) regulons largely contain known or putative metal uptake transporters from the FeoAB, NRAMP, ZIP, and TroA families. A novel family of putative iron transporters (named Irt), including multiple FetR-regulated paralogs, was identified in iron-oxidizingArchaeafrom theSulfolobalesorder. The reconstructed DtxR-TF regulons were reconciled with available transcriptomics data inArchaeoglobus,Halobacterium, andThermococcusspp.

Prolactin decreases expression of Runx2, osteoprotegerin, and RANKL in primary osteoblasts derived from tibiae of adult female rats

2008 ◽  
Vol 86 (5) ◽  
pp. 240-248 ◽  
Author(s):  
Narattaphol Charoenphandhu ◽  
Jarinthorn Teerapornpuntakit ◽  
Methajit Methawasin ◽  
Kannikar Wongdee ◽  
Kanogwun Thongchote ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Bone Cells ◽  
Nuclear Factor Κb ◽  
Clinical Findings ◽  
Female Rats ◽  
Adult Rats ◽  
Expression Of Genes ◽  
Primary Osteoblasts ◽  
Underlying Mechanisms

Hyperprolactinemia caused by physiological or pathological conditions, such as those occurring during lactation and prolactinoma, respectively, results in progressive osteopenia. The underlying mechanisms, however, are controversial. Prolactin (PRL) may directly attenuate the functions of osteoblasts, since these bone cells express PRL receptors. The present study therefore aimed to investigate the effects of PRL on the expression of genes related to the osteoblast functions by using quantitative real-time PCR technique. Herein, we used primary osteoblasts that were derived from the tibiae of adult rats and displayed characteristics of differentiated osteoblasts, including in vitro mineralization. Osteoblasts exposed for 48 h to 1000 ng/mL PRL, but not to 10 or 100 ng/mL PRL, showed decreases in the mRNA expression of Runx2, osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL) by 60.49%, 72.74%, and 87.51%, respectively. Nevertheless, PRL did not change the RANKL/OPG ratio, since expression of OPG and RANKL were proportionally decreased. These concentrations of PRL had no effect on the mRNA expression of osteocalcin and osteopontin, nor on mineralization. High pathologic concentrations of PRL (1000 ng/mL) may downregulate expression of genes that are essential for osteoblast differentiation and functions. The present results explained the clinical findings of hyperprolactinemia-induced bone loss.

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