Similar Datasets
Project description:Emerging evidence suggests that dysregulation of oncogenic pathways requires precise tuning in order for cancer to develop. To test this, we examined the overlap between cis-acting elements of the hypoxia-inducible factor (HIF) pathway and cancer-susceptibility polymorphisms as defined in genome-wide association studies (GWAS). In renal cancer, where HIF is constitutively and un-physiologically activated by mutation of the von Hippel-Lindau tumour suppressor, we observed marked excess overlap, which extended to potential susceptibility polymorphisms that are below the conventional threshold applied in GWAS. In contrast, in other cancers where HIF is upregulated by different mechanisms, including micro-environmental hypoxia, we observed no excess in overlap. Our findings support a 'pathway tuning' model of cancer, whereby precise modulation of multiple outputs of specific, activated pathways is important in oncogenesis. This implies that selective pressures to modulate such pathways operate during cancer development and should focus attempts to identify their nature and consequences.
| S-EPMC6904466 | biostudies-literature
Project description:Co-incidence of RCC-susceptibility polymorphisms with HIF cis-acting sequences supports a pathway tuning model of cancer
| PRJNA542169 | ENA
Project description:Cis-acting polymorphisms that affect gene expression are now known to be frequent, although the extent and mechanisms by which such variation affects the human phenotype are, as yet, only poorly understood. Key signatures of cis-acting variation are differences in gene expression that are tightly associated with regulatory SNPs or expression Quantitative Trait Loci (eQTL) and an imbalance of allelic expression (AEI) in heterozygous samples. Such cis-acting sequence differences appear often to have been under selection within and between populations and are also thought to be important in speciation. Here we describe the example of lactase persistence. In medical research, variants that affect regulation in cis have been implicated in both monogenic and polygenic disorders, and in the metabolism of drugs. In this review we suggest that by further understanding common regulatory variations and how they interact with other genetic and environmental variables it will be possible to gain insight into important mechanisms behind complex disease, with the potential to lead to new methods of diagnosis and treatments.
| S-EPMC3238023 | biostudies-literature
Project description:After human immunodeficiency virus type 1 (HIV-1) was identified in the early 1980s, intensive work began to understand the molecular basis of HIV-1 gene expression. Subgenomic HIV-1 RNA regions, spread throughout the viral genome, were described to have a negative impact on the nuclear export of some viral transcripts. Those studies revealed an intrinsic RNA code as a new form of nuclear export regulation. Since such regulatory regions were later also identified in other viruses, as well as in cellular genes, it can be assumed that, during evolution, viruses took advantage of them to achieve more sophisticated replication mechanisms. Here, we review HIV-1 cis-acting repressive sequences that have been identified, and we discuss their possible underlying mechanisms and importance. Additionally, we show how current bioinformatic tools might allow more predictive approaches to identify and investigate them.
| S-EPMC8274598 | biostudies-literature
Project description:Genome wide association studies frequently reveal associations between disease susceptibility and polymorphisms outside coding regions. Such associations cannot always be explained by linkage disequilibrium with changes affecting the transcription products. This has stimulated the interest in characterising sequence variation influencing gene expression levels, in particular in changes acting in cis. Differences in transcription between the two alleles at an autosomal locus can be used to test the association between candidate polymorphisms and the modulation of gene expression in cis. This type of approach requires at least one transcribed polymorphism and one candidate polymorphism. In the past five years, different methods have been proposed to analyse such data. Here we use simulations and real data sets to compare the power of some of these methods. The results show that when it is not possible to determine the phase between the transcribed and potentially cis acting allele there is some advantage in using methods that estimate phased genotype and effect on expression simultaneously. However when the phase can be determined, simple regression models seem preferable because of their simplicity and flexibility. The simulations and the analysis of experimental data suggest that in the majority of situations, methods that assume a lognormal distribution of the allelic expression ratios are both robust to deviations from this assumption and more powerful than alternatives that do not make these assumptions.
| S-EPMC3236754 | biostudies-literature
Project description:Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1? isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.
| S-EPMC5536434 | biostudies-literature
Project description:We assessed whether human transcripts expressed in an aneuploid mouse that carries human chromosome 21 (HsChr21) are spliced in a human-specific or mouse-specific fashion. In almost all cases, human-specific alternative splicing is maintained in the mouse nucleus. Species-specific splicing therefore appears to be primarily directed by cis-acting elements, rather than changes in the levels or activities of trans-acting factors. Approximately 485 million Illumina 50-nt sequence reads were generated for brain and liver tissues from normal human, Tc0 (wildtype) mouse and Tc1 mouse strains. Sequence reads were mapped to splice junctions and %in levels were estimated.
2012-12-01 | E-GEOD-31454 | biostudies-arrayexpress
Project description:Genome-wide association studies (GWAS) have become an effective tool to map genes and regions contributing to multifactorial human diseases and traits. A comparably small number of variants identified by GWAS are known to have a direct effect on protein structure whereas the majority of variants is thought to exert their moderate influences on the phenotype through regulatory changes in mRNA expression. MicroRNAs (miRNAs) have been identified as powerful posttranscriptional regulators of mRNAs. Binding to their target sites, which are mostly located within the 3'-untranslated region (3'-UTR) of mRNA transcripts, they modulate mRNA expression and stability. Until today almost all human mRNA transcripts are known to harbor at least one miRNA target site with an average of over 20 miRNA target sites per transcript. Among 5,101 GWAS-identified sentinel single nucleotide polymorphisms (SNPs) that correspond to 18,884 SNPs in linkage disequilibrium (LD) with the sentinels (r2 ? 0.8) we identified a significant overrepresentation of SNPs that affect the 3'-UTR of genes (OR?=?2.33, 95% CI?=?2.12-2.57, P < 10(-52)). This effect was even stronger considering all SNPs in one LD bin a single signal (OR?=?4.27, 95% CI?=?3.84-4.74, P < 10(-114)). Based on crosslinking immunoprecipitation data we identified four mechanisms affecting miRNA regulation by 3'-UTR mutations: (i) deletion or (ii) creation of miRNA recognition elements within validated RNA-induced silencing complex binding sites, (iii) alteration of 3'-UTR splicing leading to a loss of binding sites, and (iv) change of binding affinity due to modifications of 3'-UTR folding. We annotated 53 SNPs of a total of 288 trait-associated 3'-UTR SNPs as mediating at least one of these mechanisms. Using a qualitative systems biology approach, we demonstrate how our findings can be used to support biological interpretation of GWAS results as well as to provide new experimentally testable hypotheses.
| S-EPMC3350471 | biostudies-literature
Project description:The parts of the RNA genome of infectious bronchitis virus (IBV) required for replication and packaging of the RNA were investigated using deletion mutagenesis of a defective RNA (D-RNA) CD-61 (6.1 kb) containing a chloramphenicol acetyltransferase reporter gene. A D-RNA with the first 544, but not as few as 338, nucleotides (nt) of the 5' terminus was replicated; the 5' untranslated region (UTR) comprises 528 nt. Region I of the 3' UTR, adjacent to the nucleocapsid protein gene, comprised 212 nt and could be removed without impairment of replication or packaging of D-RNAs. A D-RNA with the final 338 nt, including the 293 nt in the highly conserved region II of the 3' UTR, was replicated. Thus, the 5'-terminal 544 nt and 3'-terminal 338 nt contained the necessary signals for RNA replication. Phylogenetic analysis of 19 strains of IBV and 3 strains of turkey coronavirus predicted a conserved stem-loop structure at the 5' end of region II of the 3' UTR. Removal of the predicted stem-loop structure abolished replication of the D-RNAs. D-RNAs in which replicase gene 1b-derived sequences had been removed or replaced with all the downstream genes were replicated well but were rescued poorly, suggesting inefficient packaging. However, no specific part of the 1b gene was required for efficient packaging.
| S-EPMC113905 | biostudies-literature
Project description:BackgroundSeveral cis-acting regulatory sequences functioning at the level of mRNA or nascent peptide and specifically influencing transcription or translation have been described. These regulatory elements often respond to specific chemicals.ResultsWe have developed a method that allows us to select cis-acting regulatory sequences that respond to diverse chemicals. The method is based on the beta-lactamase gene containing a random sequence inserted into the beginning of the ORF. Several rounds of selection are used to isolate sequences that suppress beta-lactamase expression in response to the compound under study. We have isolated sequences that respond to erythromycin, troleandomycin, chloramphenicol, meta-toluate and homoserine lactone. By introducing synonymous and non-synonymous mutations we have shown that at least in the case of erythromycin the sequences act at the peptide level. We have also tested the cross-activities of the constructs and found that in most cases the sequences respond most strongly to the compound on which they were isolated.ConclusionsSeveral selected peptides showed ligand-specific changes in amino acid frequencies, but no consensus motif could be identified. This is consistent with previous observations on natural cis-acting peptides, showing that it is often impossible to demonstrate a consensus. Applying the currently developed method on a larger scale, by selecting and comparing an extended set of sequences, might allow the sequence rules underlying the activity of cis-acting regulatory peptides to be identified.
| S-EPMC2928234 | biostudies-literature