scholarly journals Requirements for mammalian promoters to decode transcription factor dynamics

2021 ◽  
Author(s):  
Barbara Di Ventura ◽  
Enoch Boasiako Antwi ◽  
Yassine Marrakchi ◽  
Oezguen Cicek ◽  
Thomas Brox
Keyword(s):  
Mathematical Modeling ◽  
Image Analysis ◽  
Transcription Factor ◽  
Translation Initiation ◽  
Mammalian Cells ◽  
Target Genes ◽  
Optimal Strategies ◽  
Initiation Complex ◽  
Activation Dynamics ◽  
Theoretical Mechanism

In response to different stimuli many transcription factors (TFs) display different activation dynamics that trigger the expression of specific sets of target genes, suggesting that promoters have a way to decode them. Combining optogenetics, deep learning-based image analysis and mathematical modeling, we find that decoding of TF dynamics occurs only when the coupling between TF binding and transcription pre-initiation complex formation is inefficient and that the ability of a promoter to decode TF dynamics gets amplified by inefficient translation initiation. Furthermore, we propose a theoretical mechanism based on phase separation that would allow a promoter to be activated better by pulsatile than sustained TF signals. These results provide an understanding on how TF dynamics are decoded in mammalian cells, which is important to develop optimal strategies to counteract disease conditions, and suggest ways to achieve multiplexing in synthetic pathways.

scholarly journals Limits on information transduction through amplitude and frequency regulation of transcription factor activity

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Anders S Hansen ◽  
Erin K O'Shea
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Frequency Regulation ◽  
Regulation Of Transcription ◽  
Limited Information ◽  
Dynamic Information ◽  
Extrinsic Noise ◽  
Intensity Information ◽  
Single Target ◽  
Activation Dynamics

Signaling pathways often transmit multiple signals through a single shared transcription factor (TF) and encode signal information by differentially regulating TF dynamics. However, signal information will be lost unless it can be reliably decoded by downstream genes. To understand the limits on dynamic information transduction, we apply information theory to quantify how much gene expression information the yeast TF Msn2 can transduce to target genes in the amplitude or frequency of its activation dynamics. We find that although the amount of information transmitted by Msn2 to single target genes is limited, information transduction can be increased by modulating promoter cis-elements or by integrating information from multiple genes. By correcting for extrinsic noise, we estimate an upper bound on information transduction. Overall, we find that information transduction through amplitude and frequency regulation of Msn2 is limited to error-free transduction of signal identity, but not signal intensity information.

scholarly journals Max is acetylated by p300 at several nuclear localization residues

2007 ◽  
Vol 403 (3) ◽  
pp. 397-407 ◽  
Author(s):  
Francesco Faiola ◽  
Yi-Ting Wu ◽  
Songqin Pan ◽  
Kangling Zhang ◽  
Anthony Farina ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Nuclear Localization ◽  
Mammalian Cells ◽  
Target Genes ◽  
Apoptotic Cell ◽  
Central Component ◽  
Post Translational Modification ◽  
E Box

Max is a ubiquitous transcription factor with a bHLHZip [basic HLH (helix–loop–helix) leucine zipper] DNA-binding/dimerization domain and the central component of the Myc/Max/Mad transcription factor network that controls cell growth, proliferation, differentiation and apoptotic cell death in metazoans. Max is the obligatory DNA-binding and dimerization partner for all the bHLHZip regulators of the Myc/Max/Mad network, including the Myc family of oncoproteins and the Mad family of Myc antagonists, which recognize E-box DNA elements in the regulatory regions of target genes. Max lacks a transcription regulatory domain and is the only member of the network that efficiently homodimerizes. Binding of Max homodimers to E-box elements suppresses the transcription regulatory functions of its network partners and of other non-network E-box-binding regulators. In contrast with its highly regulated partners, Max is a constitutively expressed and phosphorylated protein. Phosphorylation is, however, the only Max post-translational modification identified so far. In the present study, we have analysed Max posttranslational modifications by MS. We have found that Max is acetylated at several lysine residues (Lys-57, Lys-144 and Lys-145) in mammalian cells. Max acetylation is stimulated by inhibitors of histone deacetylases and by overexpression of the p300 co-activator/HAT (histone acetyltransferase). The p300 HAT also directly acetylates Max in vitro at these three residues. Interestingly, the three Max residues acetylated in vivo and in vitro by p300 are important for Max nuclear localization and Max-mediated suppression of Myc transactivation. These results uncover novel post-translational modifications of Max and suggest the potential regulation of specific Max complexes by p300 and reversible acetylation.

Generation and Analysis of Target Genes Libraries of the Erythropoietic Transcription Factor GATA-1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1743-1743
Author(s):  
Eleni Z. Katsantoni ◽  
Sebastiaan Horsman ◽  
Michael J. Moorhouse ◽  
Victor C.L. de Jager ◽  
Peter van der Spek ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mammalian Cells ◽  
Target Genes ◽  
Genome Wide ◽  
Dna Libraries ◽  
A Genome ◽  
Search Tool ◽  
Or Gene ◽  
Novel Target

Abstract GATA-1 is essential for the generation of the erythroid, megakaryocytic, eosinophilic and mast cell lineages. It acts as an activator and repressor of different target genes. In erythroid cells it represses cell proliferation and early hematopoietic genes while activating erythroid genes. In order to elucidate further the role of GATA-1 we applied an in vivo tagging methodology for the specific, quantitative biotinylation of this factor in mammalian cells (de Boer et al., 2003). We applied this method for identification of novel target genes of GATA-1 by performing pull-downs of crosslinked chromatin using streptavidin. We have also performed chromatin immunoprecipitations, where crosslinked chromatin was immunoprecipitated with antibodies against GATA-1, thus enriching for sequences bound in vivo by this factor in the immunoprecipitated DNA. Libraries of in vivo bound DNA targets were generated and a number of clones were sequenced. In order to facilitate the bioinformatics analysis of these libraries we generated TF Target Mapper (Transcription Factors Target Mapper). This is a BLAST search tool that allows rapid extraction of annotated information on genes around each hit and combines sequence cleaning/filtering, pattern searching and comparisons of the output list of genes or gene ontology IDs with user implemented lists. This tool was successfully applied to analyze sequences bound in vivo by the transcription factor GATA-1 and efficiently extracted information on genes around ChIPed sequences, thus identifying known and potentially novel GATA-1 gene targets. Using TF Target Mapper, 95 sequences were processed and annotated information on 372 genes 50kb upstream and downstream of each hit was extracted in 27 minutes. Among these genes, known targets of GATA-1, such as α-globin and ζ-globin, were readily identified by comparing to a list of known GATA-1 targets. This work is anticipated to provide a genome wide map of GATA-1 target genes in vivo. The identification of target genes and elucidation of their functions in hematopoiesis will allow the construction of complex transcriptional pathways that control lineage commitment and differentiation decisions.

scholarly journals Interferon Regulatory Factor 5 (IRF5) Interacts with the Translation Initiation Complex and Promotes mRNA Translation During the Integrated Stress Response to Amino Acid Deprivation

2017 ◽  
Author(s):  
James D. Warner ◽  
Mandi Wiley ◽  
Ying-Y Wu ◽  
Feng Wen ◽  
Michael Kinter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Stress Response ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Initiation Complex ◽  
Cellular Processes ◽  
Interferon Regulatory Factor 5

ABSTRACTInterferon Regulatory Factor 5 (IRF5) plays an important role in limiting pathogenic infection and tumor development. Host protection by IRF5 can occur through a variety of mechanisms including production of type I interferon and cytokines as well as the regulation of cell survival, growth, proliferation, and differentiation. While modulation of these cellular processes is attributed to IRF5 transcription factor function in the nucleus, emerging evidence suggests that IRF5 may also retain non-transcriptional regulatory properties within the cytoplasmic compartment. Consistent with this notion, we report the ability of IRF5 to control gene expression at the level of mRNA translation. Our findings demonstrate that IRF5 interacts with the translation initiation complex in the absence of the m7GTP cap-binding protein, eIF4E. We observed that under nutrient deprivation-induced cell stress, IRF5 promoted mRNA translation of the master integrated stress response (ISR) regulator, Activating Transcription Factor 4 (ATF4). Enhanced ATF4 protein expression correlated with increased levels of downstream target genes including CHOP and GADD34 and was associated with amplification of eIF2α de-phosphorylation and translational de-repression under stress. The novel mechanism we describe broadens our understanding of how IRF5 regulates gene expression and may govern diverse cellular processes in the absence of stimuli that trigger IRF5 nuclear translocation.

scholarly journals In situ detection of the eIF4F translation initiation complex in mammalian cells and tissues

2021 ◽  
Vol 2 (3) ◽  
pp. 100621
Author(s):  
Shensi Shen ◽  
Isabelle Girault ◽  
Hélène Malka-Mahieu ◽  
Caroline Robert ◽  
Stéphan Vagner
Keyword(s):  
Translation Initiation ◽  
Mammalian Cells ◽  
Initiation Complex ◽  
In Situ Detection

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 Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Vishwanie S. Budhram-Mahadeo ◽  
Matthew R. Solomons ◽  
Eeshan A. O. Mahadeo-Heads
Keyword(s):  
Transcription Factor ◽  
Cardiovascular Diseases ◽  
Cell Fate ◽  
Target Genes ◽  
Cardiovascular Responses ◽  
Normal Function ◽  
Valuable Insight ◽  
Metabolic Dysfunction ◽  
Pathological Changes ◽  
Cardiac Responses

AbstractMetabolic and cardiovascular diseases are highly prevalent and chronic conditions that are closely linked by complex molecular and pathological changes. Such adverse effects often arise from changes in the expression of genes that control essential cellular functions, but the factors that drive such effects are not fully understood. Since tissue-specific transcription factors control the expression of multiple genes, which affect cell fate under different conditions, then identifying such regulators can provide valuable insight into the molecular basis of such diseases. This review explores emerging evidence that supports novel and important roles for the POU4F2/Brn-3b transcription factor (TF) in controlling cellular genes that regulate cardiometabolic function. Brn-3b is expressed in insulin-responsive metabolic tissues (e.g. skeletal muscle and adipose tissue) and is important for normal function because constitutive Brn-3b-knockout (KO) mice develop profound metabolic dysfunction (hyperglycaemia; insulin resistance). Brn-3b is highly expressed in the developing hearts, with lower levels in adult hearts. However, Brn-3b is re-expressed in adult cardiomyocytes following haemodynamic stress or injury and is necessary for adaptive cardiac responses, particularly in male hearts, because male Brn-3b KO mice develop adverse remodelling and reduced cardiac function. As a TF, Brn-3b regulates the expression of multiple target genes, including GLUT4, GSK3β, sonic hedgehog (SHH), cyclin D1 and CDK4, which have known functions in controlling metabolic processes but also participate in cardiac responses to stress or injury. Therefore, loss of Brn-3b and the resultant alterations in the expression of such genes could potentially provide the link between metabolic dysfunctions with adverse cardiovascular responses, which is seen in Brn-3b KO mutants. Since the loss of Brn-3b is associated with obesity, type II diabetes (T2DM) and altered cardiac responses to stress, this regulator may provide a new and important link for understanding how pathological changes arise in such endemic diseases.

scholarly journals Differential activation mechanisms of two isoforms of Gcr1 transcription factor generated from spliced and un-spliced transcripts in Saccharomyces cerevisiae

2020 ◽  
Author(s):  
Seungwoo Cha ◽  
Chang Pyo Hong ◽  
Hyun Ah Kang ◽  
Ji-Sook Hahn
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcription Factor ◽  
Target Genes ◽  
Gene Encoding ◽  
Metabolic Switch ◽  
Differential Activation ◽  
N Terminus ◽  
Activation Mechanisms ◽  
In Trans ◽  
Separate Activation

Abstract Gcr1, an important transcription factor for glycolytic genes in Saccharomyces cerevisiae, was recently revealed to have two isoforms, Gcr1U and Gcr1S, produced from un-spliced and spliced transcripts, respectively. In this study, by generating strains expressing only Gcr1U or Gcr1S using the CRISPR/Cas9 system, we elucidate differential activation mechanisms of these two isoforms. The Gcr1U monomer forms an active complex with its coactivator Gcr2 homodimer, whereas Gcr1S acts as a homodimer without Gcr2. The USS domain, 55 residues at the N-terminus existing only in Gcr1U, inhibits dimerization of Gcr1U and even acts in trans to inhibit Gcr1S dimerization. The Gcr1S monomer inhibits the metabolic switch from fermentation to respiration by directly binding to the ALD4 promoter, which can be restored by overexpression of the ALD4 gene, encoding a mitochondrial aldehyde dehydrogenase required for ethanol utilization. Gcr1U and Gcr1S regulate almost the same target genes, but show unique activities depending on growth phase, suggesting that these isoforms play differential roles through separate activation mechanisms depending on environmental conditions.

Sign in / Sign up

Export Citation Format

Share Document