scholarly journals General Regulatory Factors control the fidelity of transcription by restricting non-coding and ectopic initiation

2018 ◽  
Author(s):  
Drice Challal ◽  
Mara Barucco ◽  
Slawomir Kubik ◽  
Frank Feuerbach ◽  
Tito Candelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Initiation ◽  
Essential Role ◽  
Nucleosome Positioning ◽  
List Type ◽  
Control Of Gene Expression ◽  
Regulatory Factors ◽  
Non Coding Rnas ◽  
Coding Potential ◽  
Pervasive Transcription

ABSTRACTThe fidelity of transcription initiation is essential for accurate gene expression, but the determinants of start site selection are not fully understood. Rap1 and other General Regulatory Factors (GRFs) control the expression of many genes in yeast. We show that depletion of these factors induces widespread ectopic transcription initiation within promoters. This generates many novel non-coding RNAs and transcript isoforms with diverse stability, profoundly altering the coding potential of the transcriptome. Ectopic transcription initiation strongly correlates with altered nucleosome positioning. We show that Rap1 sterically constrains nucleosomes as its mere binding to the DNA can be sufficient for restoration normal nucleosome positioning, transcription initiation and gene expression. These results demonstrate an essential role for GRFs in the fidelity of transcription initiation and in the suppression of pervasive transcription, redefining current models of their function. They have general implications for the mechanism of transcription initiation and the control of gene expression.HIGHLIGHTSRap1, Abf1 and Reb1 control the fidelity of transcription initiation and suppress pervasive transcriptionWidespread ectopic transcription initiation in Rap1-deficient cells induces variegated alterations in gene expressionAltered nucleosome positioning in GRFs-defective cells correlate with ectopic transcription initiation.Rap1 controls nucleosomes positioning and transcription initiation at least partially by a steric hindrance mechanism

Abstract 286: Long Noncoding RNAs Are Differentially Expressed in Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Emma L Robinson ◽  
Syed Haider ◽  
Hillary Hei ◽  
Richard T Lee ◽  
Roger S Foo
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Significant Proportion ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Control Of Gene Expression ◽  
Failing Heart ◽  
Novel Transcripts ◽  
Non Coding Rnas

Heart failure comprises of clinically distinct inciting causes but a consistent pattern of change in myocardial gene expression supports the hypothesis that unifying biochemical mechanisms underlie disease progression. The recent RNA-seq revolution has enabled whole transcriptome profiling, using deep-sequencing technologies. Up to 70% of the genome is now known to be transcribed into RNA, a significant proportion of which is long non-coding RNAs (lncRNAs), defined as polyribonucleotides of ≥200 nucleotides. This project aims to discover whether the myocardium expression of lncRNAs changes in the failing heart. Paired end RNA-seq from a 300-400bp library of ‘stretched’ mouse myocyte total RNA was carried out to generate 76-mer sequence reads. Mechanically stretching myocytes with equibiaxial stretch apparatus mimics pathological hypertrophy in the heart. Transcripts were assembled and aligned to reference genome mm9 (UCSC), abundance determined and differential expression of novel transcripts and alternative splice variants were compared with that of control (non-stretched) mouse myocytes. Five novel transcripts have been identified in our RNA-seq that are differentially expressed in stretched myocytes compared with non-stretched. These are regions of the genome that are currently unannotated and potentially are transcribed into non-coding RNAs. Roles of known lncRNAs include control of gene expression, either by direct interaction with complementary regions of the genome or association with chromatin remodelling complexes which act on the epigenome.Changes in expression of genes which contribute to the deterioration of the failing heart could be due to the actions of these novel lncRNAs, immediately suggesting a target for new pharmaceuticals. Changes in the expression of these novel transcripts will be validated in a larger sample size of stretched myocytes vs non-stretched myocytes as well as in the hearts of transverse aortic constriction (TAC) mice vs Sham (surgical procedure without the aortic banding). In vivo investigations will then be carried out, using siLNA antisense technology to silence novel lncRNAs in mice.

Epigenetics

2019 ◽  
pp. 56-70
Author(s):  
Edward Hookway ◽  
Nicholas Athanasou ◽  
Udo Oppermann
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Tumour Suppressor Genes ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

scholarly journals Control of gene expression by glucocorticoid hormones

1984 ◽  
Vol 224 (1) ◽  
pp. 1-12 ◽  
Author(s):  
G G Rousseau
Keyword(s):  
Gene Expression ◽  
Transcription Initiation ◽  
Control Of Gene Expression ◽  
Mouse Mammary Tumour Virus ◽  
Virus Rna ◽  
Molecular Determinants ◽  
Chromatin Proteins ◽  
Modulation Of Gene Expression ◽  
Inducible Genes ◽  
Heterologous Cell

Glucocorticoids control the expression of a small number of transcriptionally active genes by increasing or decreasing mRNA concentration. Either effect can result from a transcriptional or a post-transcriptional mechanism. Induction of mouse mammary tumour virus RNA results from a stimulation of transcription initiation and depends on the presence of defined regions in proviral DNA. These regions bind the glucocorticoid receptor and behave functionally as proto-enhancers. Glucocorticoid-inducible genes can retain their sensitivity to the hormone after transfer to a heterologous cell by transfection techniques. Non-inducible genes can become inducible when linked to the promoter region of an inducible gene. The mechanisms by which the receptor-steroid complex stimulates or inhibits transcription or influences mRNA stability are unknown. Receptor binding to nucleic acids appears to be a necessary but not sufficient condition. It is likely that the receptor also interacts with chromatin proteins. This might lead to a catalytic modification of these proteins, resulting in a modulation of gene expression. Development of glucocorticoid-sensitive, biochemically defined, cell-free transcription systems should provide a tool to delineate the molecular determinants of this essential regulatory mechanism.

scholarly journals Mapping eQTLs With RNA-Seq Reveals Novel SLE Susceptibility Genes, Non-Coding RNAs, and Alternative-Splicing Events That Are Concealed Using Microarrays

2016 ◽  
Author(s):  
Christopher A. Odhams ◽  
Andrea Cortini ◽  
Lingyan Chen ◽  
Amy L. Roberts ◽  
Ana Vinuela ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Splice Junction ◽  
Susceptibility Genes ◽  
Eqtl Analysis ◽  
Rna Seq ◽  
Control Of Gene Expression ◽  
Non Coding Rnas

AbstractStudies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered a greater frequency of candidate-causal eQTLs using RNA-Seq, and identified novel SLE susceptibility genes that were concealed using microarrays (e.g. NADSYN1, SKP1, and TCF7). Many of these eQTLs were found to influence the expression of several genes, suggesting risk haplotypes may harbour multiple functional effects. We pinpointed eQTLs modulating expression of four non-coding RNAs; three of which were replicated in whole-blood. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, the autophagy-related gene WDFY4, and the redox coenzyme NADSYN1, through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. In doing so, we have identified novel SLE candidate genes and specific molecular mechanisms that will serve as the basis for targeted follow-up studies.

Non-coding RNAs: what are we missing?

2020 ◽  
Vol 98 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Cristina Carvalho Barbosa ◽  
Sydnee H. Calhoun ◽  
Hans-Joachim Wieden
Keyword(s):  
Gene Expression ◽  
External Stress ◽  
Fine Tuning ◽  
Transcriptional Level ◽  
Control Of Gene Expression ◽  
Cell Responses ◽  
The Past ◽  
Domains Of Life ◽  
Non Coding Rnas

Over the past two decades, the importance of small non-coding RNAs (sncRNAs) as regulatory molecules has become apparent in all three domains of life (archaea, bacteria, eukaryotes). In fact, sncRNAs play an important role in the control of gene expression at both the transcriptional and the post-transcriptional level, with crucial roles in fine-tuning cell responses during internal and external stress. Multiple pathways for sncRNA biogenesis and diverse mechanisms of regulation have been reported, and although biogenesis and mechanisms of sncRNAs in prokaryotes and eukaryotes are different, remarkable similarities exist. Here, we briefly review and compare the major sncRNA classes that act post-transcriptionally, and focus on recent discoveries regarding the ribosome as a target of regulation and the conservation of these mechanisms between prokaryotes and eukaryotes.

scholarly journals The Critical Role of miRNAs in Regulation of Flowering Time and Flower Development

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 319
Author(s):  
Saquib Waheed ◽  
Lihui Zeng
Keyword(s):  
Gene Expression ◽  
Flower Development ◽  
Critical Role ◽  
Transcriptional Level ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Time Of Year ◽  
Acting In Concert ◽  
Flowering Process

Flowering is an important biological process for plants that ensures reproductive success. The onset of flowering needs to be coordinated with an appropriate time of year, which requires tight control of gene expression acting in concert to form a regulatory network. MicroRNAs (miRNAs) are non-coding RNAs known as master modulators of gene expression at the post-transcriptional level. Many different miRNA families are involved in flowering-related processes such as the induction of floral competence, floral patterning, and the development of floral organs. This review highlights the diverse roles of miRNAs in controlling the flowering process and flower development, in combination with potential biotechnological applications for miRNAs implicated in flower regulation.

scholarly journals Genome organization is a major component of gene expression control in response to stress and during the cell division cycle in trypanosomes

Open Biology ◽  
2012 ◽  
Vol 2 (4) ◽  
pp. 120033 ◽  
Author(s):  
S. Kelly ◽  
S. Kramer ◽  
A. Schwede ◽  
P. K. Maini ◽  
K. Gull ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Division ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Expression Patterns ◽  
Cell Division Cycle ◽  
Control Of Gene Expression ◽  
Polycistronic Transcription ◽  
A Genome ◽  
Gene Expression Control

The trypanosome genome is characterized by RNA polymerase II-driven polycistronic transcription of protein-coding genes. Ten to hundreds of genes are co-transcribed from a single promoter; thus, selective regulation of individual genes via initiation is impossible. However, selective responses to external stimuli occur and post-transcriptional mechanisms are thought to account for all temporal gene expression patterns. We show that genes encoding mRNAs that are differentially regulated during the heat-shock response are selectively positioned in polycistronic transcription units; downregulated genes are close to transcription initiation sites and upregulated genes are distant. We demonstrate that the position of a reporter gene within a transcription unit is sufficient to reproduce this effect. Analysis of gene ontology annotations reveals that positional bias is not restricted to stress–response genes and that there is a genome-wide organization based on proximity to transcription initiation sites. Furthermore, we show that the relative abundance of mRNAs at different time points in the cell division cycle is dependent on the location of the corresponding genes to transcription initiation sites. This work provides evidence that the genome in trypanosomes is organized to facilitate co-coordinated temporal control of gene expression in the absence of selective promoters.

scholarly journals Genetic control of gene expression and splicing in the developing human brain

2018 ◽  
Author(s):  
Rebecca L. Walker ◽  
Gokul Ramaswami ◽  
Christopher Hartl ◽  
Nicholas Mancuso ◽  
Michael J. Gandal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Brain Development ◽  
Genetic Control ◽  
Allelic Variation ◽  
Fetal Brain ◽  
The Body ◽  
List Type ◽  
Control Of Gene Expression ◽  
Neuropsychiatric Diseases

SummaryMost genetic risk for human diseases lies within non-coding regions of the genome, which is predicted to regulate gene expression, often in a tissue and stage specific manner. This has motivated building of extensive eQTL resources to understand how human allelic variation affects gene expression and splicing throughout the body, focusing primarily on adult tissue. Given the importance of regulatory pathways during brain development, we characterize the genetic control of the developing human cerebral cortical transcriptome, including expression and splicing, in 201 mid-gestational human brains, to understand how common allelic variation affects gene regulation during development. We leverage expression and splice quantitative trait loci to identify genes and isoforms relevant to neuropsychiatric disorders and brain volume. These findings demonstrate genetic mechanisms by which early developmental events have a striking and widespread influence on adult anatomical and behavioral phenotypes, as well as the evolution of the human cerebral cortex.HighlightsGenome wide map of human fetal brain eQTLs and sQTLs provides a new view of genetic control of expression and splicing.There is substantial contrast between genetic control of transcript regulation in mature versus developing brain.We identify novel regulatory regions specific to fetal brain development.Integration of eQTLs and GWAS reveals specific relationships between expression and disease risk for neuropsychiatric diseases and relevant human brain phenotypes.

scholarly journals A Novel Mechanism of Antagonism between ATP-Dependent Chromatin Remodeling Complexes Regulates RNR3 Expression

2009 ◽  
Vol 29 (12) ◽  
pp. 3255-3265 ◽  
Author(s):  
Raghuvir S. Tomar ◽  
James N. Psathas ◽  
Hesheng Zhang ◽  
Zhengjian Zhang ◽  
Joseph C. Reese
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Large Subunit ◽  
Nucleosome Positioning ◽  
Gene Encoding ◽  
Control Of Gene Expression ◽  
Dna Binding Factors ◽  
Chromatin Remodeling Complexes

ABSTRACT Gene expression depends upon the antagonistic actions of chromatin remodeling complexes. While this has been studied extensively for the enzymes that covalently modify the tails of histones, the mechanism of how ATP-dependent remodeling complexes antagonize each other to maintain the proper level of gene activity is not known. The gene encoding a large subunit of ribonucleotide reductase, RNR3, is regulated by ISW2 and SWI/SNF, complexes that repress and activate transcription, respectively. Here, we studied the functional interactions of these two complexes at RNR3. Deletion of ISW2 causes constitutive recruitment of SWI/SNF, and conditional reexpression of ISW2 causes the repositioning of nucleosomes and reduced SWI/SNF occupancy at RNR3. Thus, ISW2 is required for restriction of access of SWI/SNF to the RNR3 promoter under the uninduced condition. Interestingly, the binding of sequence-specific DNA binding factors and the general transcription machinery are unaffected by the status of ISW2, suggesting that disruption of nucleosome positioning does not cause a nonspecific increase in cross-linking of all factors to RNR3. We provide evidence that ISW2 does not act on SWI/SNF directly but excludes its occupancy by positioning nucleosomes over the promoter. Genetic disruption of nucleosome positioning by other means led to a similar phenotype, linking repressed chromatin structure to SWI/SNF exclusion. Thus, incorporation of promoters into a repressive chromatin structure is essential for prevention of the opportunistic actions of nucleosome-disrupting activities in vivo, providing a novel mechanism for maintaining tight control of gene expression.

scholarly journals Orthogonal tuning of gene expression noise using CRISPR–Cas

2020 ◽  
Author(s):  
Fan Wu ◽  
Jiyoung Shim ◽  
Ting Gong ◽  
Cheemeng Tan
Keyword(s):  
Gene Expression ◽  
Reporter Gene ◽  
Transcription Initiation ◽  
Mrna Translation ◽  
Genetic Circuit ◽  
Control Of Gene Expression ◽  
Gene Expression Noise ◽  
Guide Rnas ◽  
Expression Noise ◽  
Genetic Components

Abstract The control of gene expression noise is important for improving drug treatment and the performance of synthetic biological systems. Previous work has tuned gene expression noise by changing the rate of transcription initiation, mRNA degradation, and mRNA translation. However, these methods are invasive: they require changes to the target genetic components. Here, we create an orthogonal system based on CRISPR-dCas9 to tune gene expression noise. Specifically, we modulate the gene expression noise of a reporter gene in Escherichia coli by incorporating CRISPR activation and repression (CRISPRar) simultaneously in a single cell. The CRISPRar uses a single dCas9 that recognizes two different single guide RNAs (sgRNA). We build a library of sgRNA variants with different expression activation and repression strengths. We find that expression noise and mean of a reporter gene can be tuned independently by CRISPRar. Our results suggest that the expression noise is tuned by the competition between two sgRNAs that modulate the binding of RNA polymerase to promoters. The CRISPRar may change how we tune expression noise at the genomic level. Our work has broad impacts on the study of gene functions, phenotypical heterogeneity, and genetic circuit control.

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