scholarly journals Mechanism of Metabolic Control

2000 ◽  
Vol 151 (4) ◽  
pp. 863-878 ◽  
Author(s):  
Arash Komeili ◽  
Karen P. Wedaman ◽  
Erin K. O'Shea ◽  
Ted Powers
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
De Novo ◽  
Specific Inhibitor ◽  
Nitrogen Sources ◽  
Tca Cycle ◽  
Target Of Rapamycin ◽  
Nuclear Accumulation ◽  
Cell Genome ◽  
Anaplerotic Reactions

De novo biosynthesis of amino acids uses intermediates provided by the TCA cycle that must be replenished by anaplerotic reactions to maintain the respiratory competency of the cell. Genome-wide expression analyses in Saccharomyces cerevisiae reveal that many of the genes involved in these reactions are repressed in the presence of the preferred nitrogen sources glutamine or glutamate. Expression of these genes in media containing urea or ammonia as a sole nitrogen source requires the heterodimeric bZip transcription factors Rtg1 and Rtg3 and correlates with a redistribution of the Rtg1p/Rtg3 complex from a predominantly cytoplasmic to a predominantly nuclear location. Nuclear import of the complex requires the cytoplasmic protein Rtg2, a previously identified upstream regulator of Rtg1 and Rtg3, whereas export requires the importin-β-family member Msn5. Remarkably, nuclear accumulation of Rtg1/Rtg3, as well as expression of their target genes, is induced by addition of rapamycin, a specific inhibitor of the target of rapamycin (TOR) kinases. We demonstrate further that Rtg3 is a phosphoprotein and that its phosphorylation state changes after rapamycin treatment. Taken together, these results demonstrate that target of rapamycin signaling regulates specific anaplerotic reactions by coupling nitrogen quality to the activity and subcellular localization of distinct transcription factors.

scholarly journals BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dominik Laubscher ◽  
Berkley E. Gryder ◽  
Benjamin D. Sunkel ◽  
Thorkell Andresson ◽  
Marco Wachtel ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Target Genes ◽  
De Novo ◽  
Fusion Gene ◽  
Myogenic Differentiation ◽  
Complex Function ◽  
Genome Wide ◽  
Myogenic Program

AbstractRhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define the mSWI/SNF functional repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes localize to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes, which is recapitulated by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

scholarly journals The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation

2020 ◽  
Vol 295 (50) ◽  
pp. 17158-17168
Author(s):  
Steffi Heidenreich ◽  
Pamela Weber ◽  
Heike Stephanowitz ◽  
Konstantin M. Petricek ◽  
Till Schütte ◽  
...  
Keyword(s):  
Target Genes ◽  
Metabolic Diseases ◽  
De Novo ◽  
Cell Types ◽  
Glucose Sensing ◽  
Nuclear Accumulation ◽  
Glycolytic Flux ◽  
Post Translational Modification ◽  
Element Binding Protein ◽  
Proline Hydroxylation

Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.

scholarly journals Multiple Isolated Transcription Factors Act as Switches and Contribute to Species Uniqueness

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1148
Author(s):  
Xin-Wei Zhao ◽  
Hirohisa Kishino
Keyword(s):  
Transcription Factors ◽  
Phylogenetic Trees ◽  
Target Genes ◽  
De Novo ◽  
Expression Profiles ◽  
Mammalian Species ◽  
Species Tree ◽  
Expression Levels ◽  
Species Specific

Mammals have variable numbers (1300–2000) of transcription factors (TFs), but the reasons for this large variation are unclear. To investigate general TF patterns, we de novo identified 156,906 TFs from 96 mammalian species. We identified more than 500 human isolated TFs that are rarely reported in human TF-to-TF networks. Mutations in the genes of these TFs were less lethal than those of connected TFs. Consequently, these isolated TFs are more tolerant of changes and have become unique during speciation. They may also serve as a source of variation for TF evolution. Reconciliation of TF-family phylogenetic trees with a mammalian species tree revealed an average of 37.8% TF gains and 15.0% TF losses over 177 million years, which implies that isolated TFs are pervasive in mammals. Compared with non-TF interacting genes, TF-interacting genes have unique TF profiles and have higher expression levels in mice than in humans. Different expression levels of the same TF-interacting gene contribute to species-specific phenotypes. Formation and loss of isolated TFs enabling unique TF profiles may provide variable switches that adjust divergent expression profiles of target genes to generate species-specific phenotypes, thereby making species unique.

scholarly journals BAF complexes drive proliferation and block myogenic differentiation in fusion-positive rhabdomyosarcoma

2021 ◽  
Author(s):  
Dominik Laubscher ◽  
Berkley Gryder ◽  
Benjamin Sunkel ◽  
Thorkell Andresson ◽  
Sudipto Das ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Target Genes ◽  
De Novo ◽  
Fusion Gene ◽  
Myogenic Differentiation ◽  
Complex Function ◽  
Genome Wide ◽  
Myogenic Program

Abstract Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state wile blocking terminal differentiation. Here we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance. We define, for the first time, the mSWI/SNF repertoire in FP-RMS. We find that SMARCA4 (encoding BRG1) is overexpressed in this malignancy compared to skeletal muscle and is essential for cell proliferation. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which is further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with core regulatory transcription factors. Further, mSWI/SNF complexes act as sensors of chromatin state and are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes which is reproduced by BRG1 targeting compounds. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for this lethal childhood tumor.

scholarly journals Massive loss of transcription factors and the initial diversification of placental mammals

2021 ◽  
Author(s):  
Xin-Wei Zhao ◽  
Jiaqi Wu ◽  
Hirohisa Kishino
Keyword(s):  
Transcription Factors ◽  
Regulatory Networks ◽  
Target Genes ◽  
De Novo ◽  
Expression Profiles ◽  
Mammalian Species ◽  
Gene Tree ◽  
Tree Reconciliation ◽  
Molecular Evolutionary Rates ◽  
Solitary Behavior

As one of the most successful categories of organisms, mammals occupy a variety of niches on earth as a result of macroevolution. Transcription factors (TFs), the basic regulators of gene expression, may also evolve during mammalian phenotypic diversification and macroevolution. To examine the relationship between TFs and mammalian macroevolution, we analyzed 140,821 de novo-identified TFs and their birth and death histories from 96 mammalian species. Gene tree vs. species tree reconciliation revealed that mammals experienced an upsurge in TF losses around 100 million years ago and also near the K–Pg boundary, thus implying a relationship with the divergence of placental animals. From approximately 100 million years ago to the present, losses dominated TF events without a significant change in TF gains. To quantify the effects of this TF pruning on mammalian macroevolution, we analyzed rates of molecular evolution and expression profiles of regulated target genes. Surprisingly, TF loss decelerated, rather than accelerated, molecular evolutionary rates of their target genes, suggesting increased functional constraints. Furthermore, an association study revealed that massive TF losses are significantly positively correlated with solitary behavior, nocturnality, reproductive-seasonality and insectivory life history traits, possibly through rewiring of regulatory networks.

scholarly journals Validation and characterisation of a wheat GENIE3 network using an independent RNA-Seq dataset

2019 ◽  
Author(s):  
Sophie A. Harrington ◽  
Anna E. Backhaus ◽  
Ajit Singh ◽  
Keywan Hassani-Pak ◽  
Cristobal Uauy
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Candidate Gene ◽  
Web Application ◽  
Regulatory Networks ◽  
Target Genes ◽  
De Novo ◽  
Rna Seq ◽  
Expression Levels ◽  
Biologically Relevant

AbstractGene regulatory networks are powerful tools which facilitate hypothesis generation and candidate gene discovery. However, the extent to which the network predictions are biologically relevant is often unclear. Recently, as part of an analysis of the RefSeqv1.0 wheat transcriptome, a GENIE3 network which predicted targets of wheat transcription factors was produced. Here we have used an independent and publicly-available RNA-Seq dataset to validate the predictions of the wheat GENIE3 network for the senescence-regulating transcription factor NAM-A1 (TraesCS6A02G108300). We re-analysed the RNA-Seq data against the RefSeqv1.0 genome and identified a de novo set of differentially expressed genes (DEGs) between the wild-type and nam-a1 mutant which recapitulated the known role of NAM-A1 in senescence and nutrient remobilisation. We found that the GENIE3-predicted target genes of NAM-A1 overlap significantly with the de novo DEGs, more than would be expected for a random transcription factor. Based on high levels of overlap between GENIE3-predicted target genes and the de novo DEGs, we also identified a set of candidate senescence regulators. We then explored genome-wide trends in the network related to polyploidy and homoeolog expression levels and found that only homoeologous transcription factors are likely to share predicted targets in common. However, homoeologs in dynamic triads, i.e. with higher variation in homoeolog expression levels across tissues, are less likely to share predicted targets than stable triads. This suggests that homoeologs in dynamic triads are more likely to act on distinct pathways. This work demonstrates that the wheat GENIE3 network can provide biologically-relevant predictions of transcription factor targets, which can be used for candidate gene prediction and for global analyses of transcription factor function. The GENIE3 network has now been integrated into the KnetMiner web application, facilitating its use in future studies.

scholarly journals Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

2008 ◽  
Vol 89 (5) ◽  
pp. 1131-1141 ◽  
Author(s):  
Vu Thuy Khanh Le ◽  
Mirko Trilling ◽  
Albert Zimmermann ◽  
Hartmut Hengel
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Initial Phase ◽  
Sendai Virus ◽  
Specific Inhibitor ◽  
Gene Induction ◽  
Nuclear Accumulation ◽  
Mouse Cytomegalovirus ◽  
Mcmv Infection ◽  
Beta Interferon

We have investigated beta interferon (IFN-β) and IFN-α4 gene expression and activation of related transcription factors in mouse cytomegalovirus (MCMV)-infected fibroblasts. mRNA analysis demonstrated an initial phase of IFN gene induction upon MCMV infection, which was followed by a sustained MCMV-mediated simultaneous downregulation of IFN-β and IFN-α4 gene expression. The induction of IFN transcription resulted from the activation of the components of the IFN-β enhanceosome, i.e. IFN regulatory factor (IRF) 3, nuclear factor (NF)-κB, activating transcription factor (ATF)-2 and c-Jun. Activation of the transcription factors occurred rapidly and in a sequential order upon infection, but only lasted a while. As a consequence, IFN-α/β gene expression became undetectable 6 h post-infection and throughout the MCMV replication cycle. This effect is based on an active interference since restimulation of IFN gene induction by further external stimuli (e.g. Sendai virus infection) was completely abolished. This inhibition required MCMV gene expression and was not observed in cells infected with UV-inactivated MCMV virions. The efficiency of inhibition is achieved by a concerted blockade of IκBα degradation and a lack of nuclear accumulation of IRF3 and ATF-2/c-Jun. Using an MCMV mutant lacking pM27, a signal transducer and activator of transcription (STAT) 2-specific inhibitor of Jak/STAT signalling, we found that the initial phase of IFN induction and the subsequent inhibition does not depend on the positive-IFN feedback loop. Our findings indicate that the MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a large arsenal of inhibitory mechanisms targeting each pathway that contributes to the multiprotein enhanceosome complex.

scholarly journals Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8193
Author(s):  
Daniel Pérez-Cremades ◽  
Ana B. Paes ◽  
Xavier Vidal-Gómez ◽  
Ana Mompeón ◽  
Carlos Hermenegildo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Mirna Target ◽  
Target Genes ◽  
Functional Characterization ◽  
Human Endothelial Cells ◽  
Mrna Targets ◽  
Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

scholarly journals Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro

2021 ◽  
Vol 22 (11) ◽  
pp. 5968
Author(s):  
Egor A. Turovsky ◽  
Maria V. Turovskaya ◽  
Evgeniya I. Fedotova ◽  
Alexey A. Babaev ◽  
Viktor S. Tarabykin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Nmda Receptor ◽  
Cortical Neurons ◽  
Target Genes ◽  
Cortical Cell ◽  
Inhibitory System ◽  
Selective Agonist ◽  
Genes Encoding ◽  
Deficient Mice

Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurodegenerative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Satb2 homologous factors induces the expression of genes encoding the NMDA receptor subunits, thereby leading to higher amplitudes of Ca2+-signals in neurons derived from the Satb1-deficient (Satb1fl/+ * NexCre/+) and Satb1-null mice (Satb1fl/fl * NexCre/+) in response to the selective agonist reducing the EC50 for the NMDA receptor. Simultaneously, there is an increase in the expression of the Gria2 gene, encoding the AMPA receptor subunit, thus decreasing the Ca2+-signals of neurons in response to the treatment with a selective agonist (5-Fluorowillardiine (FW)). The Satb1 deletion increases the sensitivity of the KA receptor to the agonist (domoic acid), in the cortical neurons of the Satb1-deficient mice but decreases it in the Satb1-null mice. At the same time, the Satb2 deletion decreases Ca2+-signals and the sensitivity of the KA receptor to the agonist in neurons from the Satb1-null and the Satb1-deficient mice. The Satb1 deletion affects the development of the inhibitory system of neurotransmission resulting in the suppression of the neuron maturation process and switching the GABAergic responses from excitatory to inhibitory, while the Satb2 deletion has a similar effect only in the Satb1-null mice. We show that the Satb1 and Satb2 transcription factors are involved in the regulation of the transmission of excitatory signals and inhibition of the neuronal network in the cortical cell culture.

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