Browsing by Subject "transcription factors"

Now showing 1 - 8 of 8
  • Thumbnail Image
    Item
    Coordination logic of the sensing machinery in the transcriptional regulatory network of Escherichia coli
    (2007-10) Janga, Sarath Chandra; Salgado, Heladia; Martínez-Antonio, Agustino; Collado-Vides, Julio
    The active and inactive state of transcription factors in growing cells is usually directed by allosteric physicochemical signals or metabolites, which are in turn either produced in the cell or obtained from the environment by the activity of the products of effector genes. To understand the regulatory dynamics and to improve our knowledge about how transcription factors (TFs) respond to endogenous and exogenous signals in the bacterial model, Escherichia coli, we previously proposed to classify TFs into external, internal and hybrid sensing classes depending on the source of their allosteric or equivalent metabolite. Here we analyze how a cell uses its topological structures in the context of sensing machinery and show that, while feed forward loops (FFLs) tightly integrate internal and external sensing TFs connecting TFs from different layers of the hierarchical transcriptional regulatory network (TRN), bifan motifs frequently connect TFs belonging to the same sensing class and could act as a bridge between TFs originating from the same level in the hierarchy. We observe that modules identified in the regulatory network of E. coli are heterogeneous in sensing context with a clear combination of internal and external sensing categories depending on the physiological role played by the module. We also note that propensity of two-component response regulators increases at promoters, as the number of TFs regulating a target operon increases. Finally we show that evolutionary families of TFs do not show a tendency to preserve their sensing abilities. Our results provide a detailed panorama of the topological structures of E. coli TRN and the way TFs they compose off, sense their surroundings by coordinating responses.
  • Thumbnail Image
    Item
    Dissecting the expression patterns of transcription factors across conditions using an integrated network-based approach
    (2010-07) Janga, Sarath Chandra; Contreras-Moreira, Bruno
    In prokaryotes, regulation of gene expression is predominantly controlled at the level of transcription. Transcription in turn is mediated by a set of DNA-binding factors called transcription factors (TFs). In this study, we map the complete repertoire of ∼300 TFs of the bacterial model, Escherichia coli, onto gene expression data for a number of nonredundant experimental conditions and show that TFs are generally expressed at a lower level than other gene classes. We also demonstrate that different conditions harbor varying number of active TFs, with an average of about 15% of the total repertoire, with certain stress and drug-induced conditions exhibiting as high as one-third of the collection of TFs. Our results also show that activators are more frequently expressed than repressors, indicating that activation of promoters might be a more common phenomenon than repression in bacteria. Finally, to understand the association of TFs with different conditions and to elucidate their dynamic interplay with other TFs, we develop a network-based framework to identify TFs which act as markers, defined as those which are responsible for condition-specific transcriptional rewiring. This approach allowed us to pinpoint several marker TFs as being central in various specialized conditions such as drug induction or growth condition variations, which we discuss in light of previously reported experimental findings. Further analysis showed that a majority of identified markers effectively control the expression of their regulons and, in general, transcriptional programs of most conditions can be effectively rewired by a very small number of TFs. It was also found that closeness is a key centrality measure which can aid in the successful identification of marker TFs in regulatory networks. Our results suggest the utility of the network-based approaches developed in this study to be applicable for understanding other interactomic data sets.
  • Thumbnail Image
    Item
    Identification and Genomic Analysis of Transcription Factors in Archaeal Genomes Exemplifies Their Functional Architecture and Evolutionary Origin
    (2010-02) Pérez-Rueda, Ernesto; Janga, Sarath Chandra
    Archaea, which represent a large fraction of the phylogenetic diversity of organisms, are prokaryotes with eukaryote-like basal transcriptional machinery. This organization makes the study of their DNA-binding transcription factors (TFs) and their transcriptional regulatory networks particularly interesting. In addition, there are limited experimental data regarding their TFs. In this work, 3,918 TFs were identified and exhaustively analyzed in 52 archaeal genomes. TFs represented less than 5% of the gene products in all the studied species comparable with the number of TFs identified in parasites or intracellular pathogenic bacteria, suggesting a deficit in this class of proteins. A total of 75 families were identified, of which HTH_3, AsnC, TrmB, and ArsR families were universally and abundantly identified in all the archaeal genomes. We found that archaeal TFs are significantly small compared with other protein-coding genes in archaea as well as bacterial TFs, suggesting that a large fraction of these small-sized TFs could supply the probable deficit of TFs in archaea, by possibly forming different combinations of monomers similar to that observed in eukaryotic transcriptional machinery. Our results show that although the DNA-binding domains of archaeal TFs are similar to bacteria, there is an underrepresentation of ligand-binding domains in smaller TFs, which suggests that protein–protein interactions may act as mediators of regulatory feedback, indicating a chimera of bacterial and eukaryotic TFs’ functionality. The analysis presented here contributes to the understanding of the details of transcriptional apparatus in archaea and provides a framework for the analysis of regulatory networks in these organisms.
  • Thumbnail Image
    Item
    Prediction and evolution of transcription factors and their evolutionary families in prokaryotes
    (2007-05) Janga, Sarath Chandra
    Transcription factors (TFs) play an important role in the genetic regulation of transcription in response to internal and external cellular stimulus even in a simple bacterium like Escherichia coli [1]. However little is known about their functional roles, expression dynamics and evolutionary scenarios on a large scale, even in a well studied model organisms. In this short tutorial, I will first talk about the prediction of transcription factors, which form the core of the regulatory repertoires in prokaryotes, responsible for controlling the expression of genes/transcription units by binding to their cis-regulatory regions. I will present different commonly used sequenced-based approaches to predict TFs in prokarya and discuss a simple rule of thumb to identify the putative regulatory role played by a TF based on its protein sequence alone [2-6]. I will discuss on some important properties of prokaryotic TFs which distinguish them apart from rest of the protein coding genes. The second part of the talk would concentrate on the evolutionary conservation of TFs and TF families across genomes and the implications of the observations on the phenotypic adaptation of species to different niches [3,7,8]. Finally, I will discuss some future perspectives in this area of research.
  • Thumbnail Image
    Item
    Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity
    (Springer, 2017-02) Wang, Ying; Li, Wen-Yuan; Li, Li-Xin; Deng, Ling-Xiao; Department of Neurological Surgery, IU School of Medicine
    Injury to the nervous system induces localized damage in neural structures and neuronal death through the primary insult, as well as delayed atrophy and impaired plasticity of the delicate dendritic fields necessary for interneuronal communication. Excitotoxicity and other secondary biochemical events contribute to morphological changes in neurons following injury. Evidence suggests that various transcription factors are involved in the dendritic response to injury and potential therapies. Transcription factors play critical roles in the intracellular regulation of neuronal morphological plasticity and dendritic growth and patterning. Mounting evidence supports a crucial role for epigenetic modifications via histone deacetylases, histone acetyltransferases, and DNA methyltransferases that modify gene expression in neuronal injury and repair processes. Gene regulation through epigenetic modification is of great interest in neurotrauma research, and an early picture is beginning to emerge concerning how injury triggers intracellular events that modulate such responses. This review provides an overview of injury-mediated influences on transcriptional regulation through epigenetic modification, the intracellular processes involved in the morphological consequences of such changes, and potential approaches to the therapeutic manipulation of neuronal epigenetics for regulating gene expression to facilitate growth and signaling through dendritic arborization following injury.
  • Thumbnail Image
    Item
    Transcriptional regulation shapes the organization of genes on bacterial chromosomes
    (2009-04) Janga, Sarath Chandra; Salgado, Heladia; Martínez-Antonio, Agustino
    Transcription factors (TFs) are the key elements responsible for controlling the expression of genes in bacterial genomes and when visualized on a genomic scale form a dense network of transcriptional interactions among themselves and with other protein coding genes. Although the structure of transcriptional regulatory networks (TRNs) is well understood, it is not clear what constrains govern them. Here, we explore this question using the TRNs of model prokaryotes and provide a link between the transcriptional hierarchy of regulons and their genome organization. We show that, to drive the kinetics and concentration gradients, TFs belonging to big and small regulons, depending on the number of genes they regulate, organize themselves differently on the genome with respect to their targets. We then propose a conceptual model that can explain how the hierarchical structure of TRNs might be ultimately governed by the dynamic biophysical requirements for targeting DNA-binding sites by TFs. Our results suggest that the main parameters defining the position of a TF in the network hierarchy are the number and chromosomal distances of the genes they regulate and their protein concentration gradients. These observations give insights into how the hierarchical structure of transcriptional networks can be encoded on the chromosome to drive the kinetics and concentration gradients of TFs depending on the number of genes they regulate and could be a common theme valid for other prokaryotes, proposing the role of transcriptional regulation in shaping the organization of genes on a chromosome.
  • Thumbnail Image
    Item
    Variation in a Left Ventricle–Specific Hand1 Enhancer Impairs GATA Transcription Factor Binding and Disrupts Conduction System Development and Function
    (American Heart Association, 2019-08-01) Vincentz, Joshua W.; Firulli, Beth A.; Toolan, Kevin P.; Arking, Dan E.; Sotoodehnia, Nona; Wan, Juyi; Chen, Peng-Sheng; de Gier-de Vries, Corrie; Christoffels, Vincent M.; Rubart-von der Lohe, Michael; Firulli, Anthony B.; Pediatrics, School of Medicine
    Rationale The ventricular conduction system (VCS) rapidly propagates electrical impulses through the working myocardium of the ventricles to coordinate chamber contraction. Genome-wide association studies (GWAS) have associated nucleotide polymorphisms, most are located within regulatory intergenic or intronic sequences, with variation in VCS function. Two highly correlated polymorphisms (r2>0.99) associated with VCS functional variation (rs13165478 and rs13185595) occur 5’ to the gene encoding the bHLH transcription factor HAND1. Objective Here, we test the hypothesis that these polymorphisms influence HAND1 transcription thereby influencing VCS development and function. Methods and Results We employed transgenic mouse models to identify an enhancer that is sufficient for left ventricle (LV) cis-regulatory activity. Two evolutionarily conserved GATA transcription factor cis-binding elements within this enhancer are bound by GATA4 and are necessary for cis-regulatory activity, as shown by in vitro DNA binding assays. CRISPR/Cas9-mediated deletion of this enhancer dramatically reduces Hand1 expression solely within the LV but does not phenocopy previously published mouse models of cardiac Hand1 loss-of-function. Electrophysiological and morphological analyses reveals that mice homozygous for this deleted enhancer display a morphologically abnormal VCS, and a conduction system phenotype consistent with right bundle branch block. Using 1000 Genomes Project data, we identify three additional SNPs, located within the Hand1 LV enhancer, that compose a haplotype with rs13165478 and rs13185595. One of these SNPs, rs10054375, overlaps with a critical GATA cis-regulatory element within the Hand1 LV enhancer. This SNP, when tested in electrophoretic mobility shift assays (EMSA), disrupts GATA4 DNA-binding. Modeling two of these SNPs in mice causes diminished Hand1 expression and mice present with abnormal VCS function. Conclusions Together, these findings reveal that SNP rs10054375, which is located within a necessary and sufficient LV-specific Hand1 enhancer, exhibits reduces GATA DNA-binding in EMSA and this enhancer in total, is required for VCS development and function in mice and perhaps humans.
  • Thumbnail Image
    Item
    Walk the Line: The Role of Ubiquitin in Regulating Transcription in Myocytes
    (APS, 2019-09) Suryadevara, Vidyani; Willis, Monte S.; Pathology and Laboratory Medicine, School of Medicine
    The ubiquitin-proteasome offers novel targets for potential therapies with their specific activities and tissue localization. Recently, the expansion of our understanding of how ubiquitin ligases (E3s) specifically regulate transcription has demonstrated their roles in skeletal muscle, complementing their roles in protein quality control and protein degradation. This review focuses on skeletal muscle E3s that regulate transcription factors critical to myogenesis and the maintenance of skeletal muscle wasting diseases.