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Cell Sep 2005The transcription factors OCT4, SOX2, and NANOG have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES)...
The transcription factors OCT4, SOX2, and NANOG have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have identified OCT4, SOX2, and NANOG target genes using genome-scale location analysis. We found, surprisingly, that OCT4, SOX2, and NANOG co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also indicate that OCT4, SOX2, and NANOG collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops. These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal.
Topics: Animals; Cell Differentiation; Cell Transplantation; Cells, Cultured; DNA-Binding Proteins; Embryo, Mammalian; Gene Expression Regulation, Developmental; Genes, Regulator; HMGB Proteins; Homeodomain Proteins; Humans; Mice; MicroRNAs; Nanog Homeobox Protein; Octamer Transcription Factor-3; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Protein Binding; SOXB1 Transcription Factors; Signal Transduction; Stem Cells; Transcription Factors
PubMed: 16153702
DOI: 10.1016/j.cell.2005.08.020 -
PLoS Computational Biology Jan 2022Gene networks typically involve the regulatory control of multiple genes with related function. This connectivity enables correlated control of the levels and timing of...
Gene networks typically involve the regulatory control of multiple genes with related function. This connectivity enables correlated control of the levels and timing of gene expression. Here we study how gene expression timing in the single-input module motif can be encoded in the regulatory DNA of a gene. Using stochastic simulations, we examine the role of binding affinity, TF regulatory function and network size in controlling the mean first-passage time to reach a fixed fraction of steady-state expression for both an auto-regulated TF gene and a target gene. We also examine how the variability in first-passage time depends on these factors. We find that both network size and binding affinity can dramatically speed up or slow down the response time of network genes, in some cases predicting more than a 100-fold change compared to that for a constitutive gene. Furthermore, these factors can also significantly impact the fidelity of this response. Importantly, these effects do not occur at "extremes" of network size or binding affinity, but rather in an intermediate window of either quantity.
Topics: Computer Simulation; Gene Expression Regulation; Gene Regulatory Networks; Genes, Regulator; Models, Genetic; Protein Binding; Transcription Factors
PubMed: 35041641
DOI: 10.1371/journal.pcbi.1009745 -
Proceedings of the National Academy of... Sep 2021Embryonic development leads to the reproducible and ordered appearance of complexity from egg to adult. The successive differentiation of different cell types that...
Embryonic development leads to the reproducible and ordered appearance of complexity from egg to adult. The successive differentiation of different cell types that elaborate this complexity results from the activity of gene networks and was likened by Waddington to a flow through a landscape in which valleys represent alternative fates. Geometric methods allow the formal representation of such landscapes and codify the types of behaviors that result from systems of differential equations. Results from Smale and coworkers imply that systems encompassing gene network models can be represented as potential gradients with a Riemann metric, justifying the Waddington metaphor. Here, we extend this representation to include parameter dependence and enumerate all three-way cellular decisions realizable by tuning at most two parameters, which can be generalized to include spatial coordinates in a tissue. All diagrams of cell states vs. model parameters are thereby enumerated. We unify a number of standard models for spatial pattern formation by expressing them in potential form (i.e., as topographic elevation). Turing systems appear nonpotential, yet in suitable variables the dynamics are low dimensional and potential. A time-independent embedding recovers the original variables. Lateral inhibition is described by a saddle point with many unstable directions. A model for the patterning of the eye appears as relaxation in a bistable potential. Geometric reasoning provides intuitive dynamic models for development that are well adapted to fit time-lapse data.
Topics: Animals; Cell Differentiation; Drosophila; Gene Regulatory Networks; Genes, Regulator; Models, Genetic
PubMed: 34518231
DOI: 10.1073/pnas.2109729118 -
Molecular Microbiology Feb 2017Data from multiple bacterial pathogens are consistent with regulator-encoding genes having higher mutation frequencies than the genome average. Such mutations drive both... (Review)
Review
Data from multiple bacterial pathogens are consistent with regulator-encoding genes having higher mutation frequencies than the genome average. Such mutations drive both strain- and type- (e.g., serotype, haplotype) specific phenotypic heterogeneity, and may challenge public health due to the potential of variants to circumvent established treatment and/or preventative regimes. Here, using the human bacterial pathogen the group A Streptococcus (GAS; S. pyogenes) as a model organism, we review the types and regulatory-, phenotypic-, and disease-specific consequences of naturally occurring regulatory gene mutations. Strain-specific regulator mutations that will be discussed include examples that transform isolates into hyper-invasive forms by enhancing expression of immunomodulatory virulence factors, and examples that promote asymptomatic carriage of the organism. The discussion of serotype-specific regulator mutations focuses on serotype M3 GAS isolates, and how the identified rewiring of regulatory networks in this serotype may be contributing to a decades old epidemiological association of M3 isolates with particularly severe invasive infections. We conclude that mutation plays an outsized role in GAS pathogenesis and has clinical relevance. Given the phenotypic variability associated with regulatory gene mutations, the rapid examination of these genes in infecting isolates may inform with respect to potential patient complications and treatment options.
Topics: Gene Expression Regulation, Bacterial; Genes, Regulator; Genome, Bacterial; Humans; Mutation; Serogroup; Streptococcal Infections; Streptococcus pyogenes; Virulence Factors
PubMed: 27868255
DOI: 10.1111/mmi.13584 -
Trends in Neurosciences Oct 2010Neuron-type specific gene batteries define the morphological and functional diversity of cell types in the nervous system. Here, we discuss the composition of... (Review)
Review
Neuron-type specific gene batteries define the morphological and functional diversity of cell types in the nervous system. Here, we discuss the composition of neuron-type specific gene batteries and illustrate gene regulatory strategies which determine the unique gene expression profiles and molecular composition of individual neuronal cell types from C. elegans to higher vertebrates. Based on principles learned from prokaryotic gene regulation, we argue that neuronal terminal gene batteries are functionally grouped into parallel-acting 'regulons'. The theoretical concepts discussed here provide testable hypotheses for future experimental analysis of the exact gene-regulatory mechanisms employed in the generation of neuronal diversity and identity.
Topics: Animals; Cell Differentiation; Gene Expression Profiling; Gene Expression Regulation; Genes, Regulator; Humans; Molecular Sequence Data; Neurons; Regulatory Elements, Transcriptional
PubMed: 20663572
DOI: 10.1016/j.tins.2010.05.006 -
Communications Biology Sep 2020Regulatory genes are often multifunctional and constrained, which results in evolutionary conservation. It is difficult to understand how a regulatory gene could be lost...
Regulatory genes are often multifunctional and constrained, which results in evolutionary conservation. It is difficult to understand how a regulatory gene could be lost from one species' genome when it is essential for viability in closely related species. The gene paired is a classic Drosophila pair-rule gene, required for formation of alternate body segments in diverse insect species. Surprisingly, paired was lost in mosquitoes without disrupting body patterning. Here, we demonstrate that a paired family member, gooseberry, has acquired paired-like expression in the malaria mosquito Anopheles stephensi. Anopheles-gooseberry CRISPR-Cas9 knock-out mutants display pair-rule phenotypes and alteration of target gene expression similar to what is seen in Drosophila and beetle paired mutants. Thus, paired was functionally replaced by the related gene, gooseberry, in mosquitoes. Our findings document a rare example of a functional replacement of an essential regulatory gene and provide a mechanistic explanation of how such loss can occur.
Topics: Animals; Anopheles; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Conserved Sequence; Drosophila; Drosophila Proteins; Female; Gene Deletion; Gene Editing; Gene Expression Regulation; Gene Regulatory Networks; Genes, Essential; Genes, Insect; Genes, Regulator; Male; Nuclear Proteins; Phylogeny; Sequence Alignment; Trans-Activators
PubMed: 32999445
DOI: 10.1038/s42003-020-01203-w -
Cells Sep 2021Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is...
Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is crucial in devising targeted treatment options. Expression quantitative trait locus (eQTL) analysis correlates a genetic variant with the strength of gene expression, thus defining thousands of regulated genes in a multitude of human cell types and tissues. Some eQTL may not act independently of each other but instead may be regulated in a coordinated fashion by seemingly independent genetic variants. To address this issue, we combined the approaches of eQTL analysis and colocalization studies. Gene expression was determined in datasets comprising 49 tissues from the Genotype-Tissue Expression (GTEx) project. From about 33,000 regulated genes, over 14,000 were found to be co-regulated in pairs and were assembled across all tissues to almost 15,000 unique clusters containing up to nine regulated genes affected by the same eQTL signal. The distance of co-regulated eGenes was, on average, 112 kilobase pairs. Of 713 genes known to express clinical symptoms upon haploinsufficiency, 231 (32.4%) are part of at least one of the identified clusters. This calls for caution should treatment approaches aim at an upregulation of a haploinsufficient gene. In conclusion, we present an unbiased approach to identifying co-regulated genes in and across multiple tissues. Knowledge of such common effects is crucial to appreciate implications on biological pathways involved, specifically when a treatment option targets a co-regulated disease gene.
Topics: Computational Biology; Gene Expression Profiling; Genes, Regulator; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multigene Family; Polymorphism, Single Nucleotide; Quantitative Trait Loci
PubMed: 34572044
DOI: 10.3390/cells10092395 -
BioEssays : News and Reviews in... Jan 2018Transposable elements (TEs) are no longer considered to be "junk" DNA. Here, we review how TEs can impact gene regulation systematically. TEs encode various regulatory... (Review)
Review
Transposable elements (TEs) are no longer considered to be "junk" DNA. Here, we review how TEs can impact gene regulation systematically. TEs encode various regulatory elements that enables them to regulate gene expression. RJ Britten and EH Davidson hypothesized that TEs can integrate the function of various transcriptional regulators into gene regulatory networks. Uniquely TEs can deposit regulatory sites across the genome when they transpose, and thereby bring multiple genes under control of the same regulatory logic. Several studies together have robustly established that TEs participate in embryonic development and oncogenesis. We discuss the regulatory characteristics of TEs in context of evolution to understand the extent of their impact on gene networks. Understanding these features of TEs is central to future investigations of TEs in cellular processes and phenotypic presentations, which are applicable to development and disease studies. We re-visit the Britten-Davidson "gene-battery" model and understand the genetic and transcriptional impact of TEs in innovating gene regulatory networks.
Topics: Binding Sites; DNA Transposable Elements; Evolution, Molecular; Gene Expression Regulation; Gene Regulatory Networks; Genes, Regulator; Genome, Human; Humans; Models, Molecular; Phenotype; Transcription Factors
PubMed: 29206283
DOI: 10.1002/bies.201700155 -
EBioMedicine Jul 2022Streptococcus dysgalactiae subspecies equisimilis (SDSE) has emerged as an important cause of severe invasive infections including streptococcal toxic shock syndrome...
Natural mutation in the regulatory gene (srrG) influences virulence-associated genes and enhances invasiveness in Streptococcus dysgalactiae subsp. equisimilis strains isolated from cases of streptococcal toxic shock syndrome.
BACKGROUND
Streptococcus dysgalactiae subspecies equisimilis (SDSE) has emerged as an important cause of severe invasive infections including streptococcal toxic shock syndrome (STSS). The present study aimed to identify genes involved in differences in invasiveness between STSS and non-invasive SDSE isolates.
METHODS
STSS and non-invasive SDSE isolates were analysed to identify csrS/csrR mutations, followed by a comparative analysis of genomic sequences to identify mutations in other genes. Mutant strains were generated to examine changes in gene expression profiles and altered pathogenicity in mice.
FINDINGS
Of the 79 STSS-SDSE clinical isolates, 15 (19.0%) harboured csrS/csrR mutations, while none were found in the non-invasive SDSE isolates. We identified a small RNA (sRNA) that comprised three direct repeats along with an inverted repeat and was transcribed in the same direction as the sagA gene. The sRNA was referred to as srrG (streptolysin S regulatory RNA in GGS). srrG mutations were identified in the STSS-SDSE strains and were found to be associated with elevated expression of the streptolysin S (SLS) gene cluster and enhanced pathogenicity in mice.
INTERPRETATION
The csrS/csrR and srrG mutations that increased virulence gene expression in STSS-SDSE isolates were identified, and strains carrying these mutations caused increased lethality in mice. A significantly higher frequency of mutations was observed in STSS-SDSE isolates, thereby highlighting their importance in STSS.
FUNDING
Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science (JSPS), and the Ministry of Health, Labor, and Welfare of Japan.
Topics: Animals; Genes, Regulator; Mice; Mutation; RNA, Small Untranslated; Shock, Septic; Streptococcal Infections; Streptococcus; Streptolysins; Virulence
PubMed: 35779495
DOI: 10.1016/j.ebiom.2022.104133 -
Microbiological Research Nov 2020Bitespiramycin (biotechnological spiramycin, Bsm) is a new 16-membered macrolide antibiotic produced by Streptomyces spiramyceticus WSJ-1 integrated exogenous genes. The...
Bitespiramycin (biotechnological spiramycin, Bsm) is a new 16-membered macrolide antibiotic produced by Streptomyces spiramyceticus WSJ-1 integrated exogenous genes. The gene cluster for Bsm biosynthesis consists of two parts: spiramycin biosynthetic gene cluster (92 kb) and two exogenous genes including 4"-O-isovaleryltransferase gene (ist) and a positive regulatory gene (acyB2) from S. thermotolerans. Four putative regulatory genes, bsm2, bsm23, bsm27 and bsm42, were identified by sequence analysis in the spiramycin gene cluster. The inactivation of bsm23 or bsm42 in S. spiramyceticus eliminated spiramycin production, while the deletion of bsm2 and bsm27 did not abolish spiramycin biosynthesis. The acyB2 gene, homologous with bsm42 gene, cannot recover the spiramycin production in Δbsm42 mutant. The high expression of bsm42 significantly increased the spiramycin production, but overexpression of bsm23 inhibited its production in Δbsm23 and wild-type strain. Bsm23 was shown to be involved in the regulation of the expression of bsm42 and acyB2 by electrophoretic mobility shift assays. The bsm42 gene was also positive regulator for ist expression inferred from the improved yield of 4"-isovalerylspiramycins in the S. lividans TK24 biotransformation test, but adding bsm23 decreased the production of 4''-isovalerylspiramycins. These results demonstrated Bsm42 was a pathway-specific activator for spiramycin or Bsm biosynthesis, but overexpression of Bsm23 alone was adverse to produce these antibiotics although Bsm23 was essential for positive regulation of spiramycin production.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Biosynthetic Pathways; Biotransformation; Gene Expression Regulation, Bacterial; Genes, Regulator; Multigene Family; Spiramycin; Streptomyces
PubMed: 32622100
DOI: 10.1016/j.micres.2020.126532