scholarly journals Promoter sequence and architecture determine expression variability and confer robustness to genetic variants

2021 ◽  
Author(s):  
Hjorleifur Einarsson ◽  
Marco Salvatore ◽  
Christian Vaagenso ◽  
Nicolas Alcaraz ◽  
Jette Bornholdt Lange ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Binding Sites ◽  
Promoter Sequence ◽  
Effect Sizes ◽  
Regulatory Mechanisms ◽  
Transcription Start ◽  
Mutational Robustness ◽  
Expression Variability ◽  
Transcription Start Sites ◽  
The Relationship

Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability is largely determined by a promoter's DNA sequence and its binding sites for specific transcription factors. We further demonstrate that flexible usage of transcription start sites within a promoter attenuates variability, providing transcriptional and mutational robustness.

scholarly journals Genome-Wide Identification of Transcription Start Sites, Promoters and Transcription Factor Binding Sites in E. coli

PLoS ONE ◽  
2009 ◽  
Vol 4 (10) ◽  
pp. e7526 ◽  
Author(s):  
Alfredo Mendoza-Vargas ◽  
Leticia Olvera ◽  
Maricela Olvera ◽  
Ricardo Grande ◽  
Leticia Vega-Alvarado ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
E Coli ◽  
Factor Binding ◽  
Genome Wide

Structural organization of upstream exons and distribution of transcription start sites in the chicken c-myb gene

1989 ◽  
Vol 9 (2) ◽  
pp. 837-843
Author(s):  
S L Hahn ◽  
M Hahn ◽  
W S Hayward
Keyword(s):  
Binding Sites ◽  
Noncoding Region ◽  
Open Reading Frames ◽  
Transcription Start ◽  
S1 Nuclease ◽  
Transcription Start Sites ◽  
Conserved Sequence ◽  
Myb Gene ◽  
Putative Transcription Factor ◽  
Myb Genes

We mapped and sequenced three upstream exons of the chicken c-myb gene and the regions flanking the first coding exon. We found multiple potential binding sites for transcription factors in the 5'-noncoding region, a T-rich stretch of 78 base pairs (bp) (68% T) in the first intron, and four fairly long open reading frames in the antisense direction of the first coding exon and its flanking regions. Three major transcription start sites, contained within a single 11-bp region, were identified by S1 nuclease analysis and primer extension. A sequence comparison of the avian and murine c-myb genes revealed a highly conserved sequence of 124 bp in the 5'-noncoding region. Its location between the putative transcription factor binding sites and the major transcription start sites suggests that it may play an important regulatory role in c-myb expression.

scholarly journals Genome-Wide Identification of Estrogen Receptor α-Binding Sites in Mouse Liver

2008 ◽  
Vol 22 (1) ◽  
pp. 10-22 ◽  
Author(s):  
Hui Gao ◽  
Susann Fält ◽  
Albin Sandelin ◽  
Jan-Åke Gustafsson ◽  
Karin Dahlman-Wright
Keyword(s):  
Estrogen Receptor ◽  
Binding Sites ◽  
Mouse Liver ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Transcription Start ◽  
Expression Levels ◽  
Transcription Start Sites ◽  
Genome Wide ◽  
Binding Regions

Abstract We report the genome-wide identification of estrogen receptor α (ERα)-binding regions in mouse liver using a combination of chromatin immunoprecipitation and tiled microarrays that cover all nonrepetitive sequences in the mouse genome. This analysis identified 5568 ERα-binding regions. In agreement with what has previously been reported for human cell lines, many ERα-binding regions are located far away from transcription start sites; approximately 40% of ERα-binding regions are located within 10 kb of annotated transcription start sites. Almost 50% of ERα-binding regions overlap genes. The majority of ERα-binding regions lie in regions that are evolutionarily conserved between human and mouse. Motif-finding algorithms identified the estrogen response element, and variants thereof, together with binding sites for activator protein 1, basic-helix-loop-helix proteins, ETS proteins, and Forkhead proteins as the most common motifs present in identified ERα-binding regions. To correlate ERα binding to the promoter of specific genes, with changes in expression levels of the corresponding mRNAs, expression levels of selected mRNAs were assayed in livers 2, 4, and 6 h after treatment with ERα-selective agonist propyl pyrazole triol. Five of these eight selected genes, Shp, Stat3, Pdgds, Pck1, and Pdk4, all responded to propyl pyrazole triol after 4 h treatment. These results extend our previous studies using gene expression profiling to characterize estrogen signaling in mouse liver, by characterizing the first step in this signaling cascade, the binding of ERα to DNA in intact chromatin.

scholarly journals Evidence for Evolutionary and Nonevolutionary Forces Shaping the Distribution of Human Genetic Variants near Transcription Start Sites

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e114432 ◽  
Author(s):  
Giovanni Scala ◽  
Ornella Affinito ◽  
Gennaro Miele ◽  
Antonella Monticelli ◽  
Sergio Cocozza
Keyword(s):  
Genetic Variants ◽  
Transcription Start ◽  
Transcription Start Sites

scholarly journals ExsA Recruits RNA Polymerase to an Extended −10 Promoter by Contacting Region 4.2 of Sigma-70

2010 ◽  
Vol 192 (14) ◽  
pp. 3597-3607 ◽  
Author(s):  
Christopher A. Vakulskas ◽  
Evan D. Brutinel ◽  
Timothy L. Yahr
Keyword(s):  
Rna Polymerase ◽  
Binding Sites ◽  
Type Iii Secretion ◽  
Transcription Initiation ◽  
Additional Contribution ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Collective Data ◽  
Sigma 70

ABSTRACT ExsA is a member of the AraC family of transcriptional activators and is required for expression of the Pseudomonas aeruginosa type III secretion system (T3SS). ExsA-dependent promoters consist of two binding sites for monomeric ExsA located approximately 50 bp upstream of the transcription start sites. Binding to both sites is required for recruitment of σ70-RNA polymerase (RNAP) to the promoter. ExsA-dependent promoters also contain putative −35 hexamers that closely match the σ70 consensus but are atypically spaced 21 or 22 bp from the −10 hexamer. Because several nucleotides located within the putative −35 region are required for ExsA binding, it is unclear whether the putative −35 region makes an additional contribution to transcription initiation. In the present study we demonstrate that the putative −35 hexamer is dispensable for ExsA-independent transcription from the P exsC promoter and that deletion of σ70 region 4.2, which contacts the −35 hexamer, has no effect on ExsA-independent transcription from P exsC . Region 4.2 of σ70, however, is required for ExsA-dependent activation of the P exsC and P exsD promoters. Genetic data suggest that ExsA directly contacts region 4.2 of σ70, and several amino acids were found to contribute to the interaction. In vitro transcription assays demonstrate that an extended −10 element located in the P exsC promoter is important for overall promoter activity. Our collective data suggest a model in which ExsA compensates for the lack of a −35 hexamer by interacting with region 4.2 of σ70 to recruit RNAP to the promoter.

scholarly journals Accurate transcription start sites enable mining for the cis-regulatory determinants of tissue specific gene expression

2020 ◽  
Author(s):  
Mitra Ansariola ◽  
Valerie N. Fraser ◽  
Sergei A. Filichkin ◽  
Maria G. Ivanchenko ◽  
Zachary A. Bright ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Open Chromatin ◽  
Transcription Start ◽  
Tissue Specific ◽  
Transcription Start Sites ◽  
Tissue Specific Gene ◽  
Specific Gene Expression

AbstractAcross tissues, gene expression is regulated by a combination of determinants, including the binding of transcription factors (TFs), along with other aspects of cellular state. Recent studies emphasize the importance of both genetic and epigenetic states – TF binding sites and binding site chromatin accessibility have emerged as potentially causal determinants of tissue specificity. To investigate the relative contributions of these determinants, we constructed three genome-scale datasets for both root and shoot tissues of the same Arabidopsis thaliana plants: TSS-seq data to identify Transcription Start Sites, OC-seq data to identify regions of Open Chromatin, and RNA-seq data to assess gene expression levels. For genes that are differentially expressed between root and shoot, we constructed a machine learning model predicting tissue of expression from chromatin accessibility and TF binding information upstream of TSS locations. The resulting model was highly accurate (over 90% auROC and auPRC), and our analysis of model contributions (feature weights) strongly suggests that patterns of TF binding sites within ∼500 nt TSS-proximal regions are predominant explainers of tissue of expression in most cases. Thus, in plants, cis-regulatory control of tissue-specific gene expression appears to be primarily determined by TSS-proximal sequences, and rarely by distal enhancer-like accessible chromatin regions. This study highlights the exciting future possibility of a native TF site-based design process for the tissue-specific targeting of plant gene promoters.

scholarly journals Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+exchanger gene

1998 ◽  
Vol 274 (1) ◽  
pp. H217-H232 ◽  
Author(s):  
Susanne B. Nicholas ◽  
Weidong Yang ◽  
Shwu-Luan Lee ◽  
Hong Zhu ◽  
Kenneth D. Philipson ◽  
...  
Keyword(s):  
Binding Sites ◽  
Alternative Promoters ◽  
Limited Data ◽  
Transcription Start ◽  
Specific Expression ◽  
Tissue Specific ◽  
Transcription Start Sites ◽  
Gata Factors ◽  
Specific Alternative ◽  
Specific Factors

Many studies have investigated the regulation of the Na+/Ca2+exchanger, NCX1, but limited data exist on transcriptional regulation of the NCX1 gene. We have identified the transcription start sites of three tissue-specific alternative promoters of NCX1 transcripts from rat heart, kidney, and brain. We have characterized the cardiac NCX1 promoter, from which the most abundant quantities of NCX1 transcripts are expressed. Transfection of primary cardiac myocytes, CHO cells, and COS-7 cells with overlapping genomic DNA fragments spanning the NCX1 cardiac transcription start site has uncovered a cardiac cell-specific minimum promoter from −137 to +85. The cardiac NCX1 promoter is TATA-less but has putative binding sites for cardiac-specific GATA factors, an E box, and an Inr as well as multiple active enhancers. The kidney NCX1 promoter has a typical TATA box and binding sites for several tissue-specific factors. The brain NCX1 promoter is very GC-rich and possesses several Sp-1 binding sites consistent with its ubiquitous expression.

scholarly journals Transcriptional regulation of Pseudomonas aeruginosa rhlR: role of the CRP orthologue Vfr (virulence factor regulator) and quorum-sensing regulators LasR and RhlR

Microbiology ◽  
2011 ◽  
Vol 157 (9) ◽  
pp. 2545-2555 ◽  
Author(s):  
Gerardo Croda-García ◽  
Victoria Grosso-Becerra ◽  
Abigail Gonzalez-Valdez ◽  
Luis Servín-González ◽  
Gloria Soberón-Chávez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Transcriptional Regulation ◽  
Quorum Sensing ◽  
Binding Sites ◽  
Regulatory Network ◽  
Coding Region ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Negative Effect

The production of many virulence factors by Pseudomonas aeruginosa is regulated by the quorum-sensing (QS) response. In this regulatory network LasR and RhlR, bound to their corresponding autoinducers, play a central role. The QS response has a hierarchical structure: LasR/3O-C12-HSL activates the transcription of rhlR, and RhlR/C4-HSL activates the transcription of several genes, including the rhlAB operon, which encodes the enzymes responsible for rhamnolipid synthesis. The rhlAB operon is located immediately upstream of the rhlR gene. rhlR has four transcription start sites, two of which are located in the rhlB coding region. Vfr directly activates transcription of lasR, and has been reported to be also involved in rhlR expression. The aim of this work was to characterize the details of the mechanism of rhlR transcriptional regulation. We show that Vfr directly regulates rhlR transcription through its binding to several Vfr-binding sites (VBSs) present in the rhlR promoter region, one of which has a negative effect on transcription. Two of the VBSs overlap with las boxes where LasR/3O-C12-HSL binds to activate rhlR transcription. We also show that rhlR transcription is subject to positive-feedback autoregulation through RhlR/C4-HSL activation of the rhlA promoter. This positive autoregulation plays a major role in rhlR expression.

scholarly journals Dual Promoters Control Expression of the Bacillus anthracis Virulence Factor AtxA

2008 ◽  
Vol 190 (19) ◽  
pp. 6483-6492 ◽  
Author(s):  
Cristina Bongiorni ◽  
Tatsuya Fukushima ◽  
Adam C. Wilson ◽  
Christina Chiang ◽  
M. Cecilia Mansilla ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Sigma Factor ◽  
Promoter Activity ◽  
Regulatory Mechanisms ◽  
Phosphotransferase System ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Consensus Sequences ◽  
Dual Promoters ◽  
Virulence Regulator

ABSTRACT The AtxA virulence regulator of Bacillus anthracis is required for toxin and capsule gene expression. AtxA is a phosphotransferase system regulatory domain-containing protein whose activity is regulated by phosphorylation/dephosphorylation of conserved histidine residues. Here we report that transcription of the atxA gene occurs from two independent promoters, P1 (previously described by Dai et al. [Z. Dai, J. C. Sirard, M. Mock, and T. M. Koehler, Mol. Microbiol. 16:1171-1181, 1995]) and P2, whose transcription start sites are separated by 650 bp. Both promoters have −10 and −35 consensus sequences compatible with recognition by σA-containing RNA polymerase, and neither promoter depends on the sporulation sigma factor SigH. The dual promoter activity and the extended untranslated mRNA suggest that as-yet-unknown regulatory mechanisms may act on this region to influence the level of AtxA in the cell.

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