cis-Acting regulatory elements in the GAP-43 mRNA 3′-untranslated region can function in trans to suppress endogenous GAP-43 gene expression

1999 ◽  
Vol 65 (1) ◽  
pp. 52-60 ◽  
Author(s):  
Rachael L. Neve ◽  
Kathryn J. Ivins ◽  
Kao-Chung Tsai ◽  
Sherry L. Rogers ◽  
Nora I. Perrone-Bizzozero
Keyword(s):  
Gene Expression ◽  
Untranslated Region ◽  
Regulatory Elements ◽  
Cis Acting ◽  
In Trans

scholarly journals CFTR Cooperative Cis-Regulatory Elements in Intestinal Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2599
Author(s):  
Mégane Collobert ◽  
Ozvan Bocher ◽  
Anaïs Le Nabec ◽  
Emmanuelle Génin ◽  
Claude Férec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Gene Regulation ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Cftr Gene ◽  
Intestinal Cells ◽  
Cooperative Effects ◽  
Cis Acting ◽  
Study Techniques

About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator (CFTR) regulatory elements were identified, but the regulatory mechanisms of the CFTR gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the CFTR gene regulation, and to identity factors that could impact the CFTR gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as CFTR-related disorders. Here, we apply the robust GWAS3D score to determine which of the CFTR introns could be involved in gene regulation. This approach highlights four particular CFTR introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the CFTR gene regulation and allow us to suggest a 3D CFTR locus structure in intestinal cells. A better understand of regulation mechanisms of the CFTR gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These cis-acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future.

cis-acting elements involved in the alternative translation initiation process of human basic fibroblast growth factor mRNA

1992 ◽  
Vol 12 (10) ◽  
pp. 4796-4805
Author(s):  
A C Prats ◽  
S Vagner ◽  
H Prats ◽  
F Amalric
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Untranslated Region ◽  
Specific Effect ◽  
Regulatory Elements ◽  
Fibroblast Growth ◽  
Cis Acting ◽  
Initiation Of Translation ◽  
Alternative Translation

Four forms of basic fibroblast growth factor (bFGF) are synthesized from the same mRNA, resulting from alternative initiations of translation at three CUG start codons and one AUG start codon. The CUG- and AUG-initiated forms have distinct intracellular localizations and can modify cell phenotypes differently, indicating that control of the alternative expression of the different forms of bFGF has an important impact on the cell. In this study, we investigated the roles of the mRNA 5' untranslated region and the alternatively translated region located between the CUG and AUG codons in the regulation of alternative translation of the different forms of bFGF. Deletions and site-directed mutagenesis were carried out in bFGF mRNA leader, and translation was studied in vitro and in vivo. The results enabled us to identify five cis-acting RNA elements (two in the 5' untranslated region and three in the alternatively translated region) involved in the regulation of either global or alternative initiation of translation. Each of these elements had a specific effect on the level of synthesis of the different forms of bFGF. Furthermore, we showed that the 5' untranslated region regulatory elements had different effects on bFGF translation, depending on the translation system used. These results suggest that bFGF translation is modulated by cis-acting elements corresponding to secondary or tertiary RNA structures, which could be the targets of cell-specific trans-acting factors.

Factors Involved in the Regulation of Type I Collagen Gene Expression: Implication in Fibrosis

2002 ◽  
Vol 227 (5) ◽  
pp. 301-314 ◽  
Author(s):  
Asish K. Ghosh
Keyword(s):  
Gene Expression ◽  
Collagen Synthesis ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Regulatory Elements ◽  
Transcriptional Level ◽  
Type I ◽  
Collagen Gene ◽  
Cis Acting ◽  
Collagen Gene Expression

Type I collagen, the major component of extracellular matrix in skin and other tissues, is a heterotrimer of two α1 and one α2 collagen polypeptides. The synthesis of both chains is highly regulated by different cytokines at the transcriptional level. Excessive synthesis and deposition of collagen in the dermal region causes thick and hard skin, a clinical manifestation of scleroderma. To better understand the causes of scleroderma or other tissue fibrosis, it is very Important to investigate the molecular mechanisms that cause upregulation of the Type I collagen synthesis in these tissues. Several cis-acting regulatory elements and trans-acting protein factors, which are involved in basal as well as cytokine-modulated Type I collagen gene expression, have been identified and characterized. Hypertranscription of Type I collagen in scleroderma skin fibroblasts may be due to abnormal activities of different positive or negative transcription factors In response to different abnormally induced signaling pathways. In this review, I discuss the present day understanding about the involvement of different factors in the regulation of basal as well as cytokine-modulated Type I collagen gene expression and its implication in scleroderma research.

Immunoglobulin molecular genetics: the prospects for mutational analysis of the chromosomal immunoglobulin genes

Genome ◽  
1989 ◽  
Vol 31 (1) ◽  
pp. 175-181 ◽  
Author(s):  
Marc J. Shulman ◽  
Lucine Bosnoyan ◽  
Catherine Collins ◽  
Nancy Pennell ◽  
Mark D. Baker
Keyword(s):  
Gene Expression ◽  
Homologous Recombination ◽  
Mutational Analysis ◽  
Regulatory Elements ◽  
Hybridoma Cells ◽  
Immunoglobulin Genes ◽  
Chromosomal Dna ◽  
Cis Acting ◽  
Chromosomal Genes ◽  
Recombination Gene

Homologous recombination between transferred and chromosomal DNA can be used to effect precise, predetermined modifications of the chromosomal genes. Ultimately this phenomenon should allow the assessment of genetic regulatory elements as they function in the normal chromosomal environment. We have previously described a system for isolating mutant hybridoma cells that are defective in immunoglobulin (Ig) production, with a view toward using these mutants to define cis-acting elements that influence Ig gene expression. Here we describe results that indicate that homologous recombination between transferred and chromosomal Ig genes can be used to map Ig mutations by marker rescue.Key words: homologous recombination, gene expression.

scholarly journals Bimodal sequence composition underlies functional duality of transcribed enhancers

2020 ◽  
Author(s):  
Mario Flores ◽  
Ivan Ovcharenko
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Regulatory Elements ◽  
Mechanisms Of Action ◽  
Sequence Composition ◽  
Helix Formation ◽  
Evolutionarily Conserved ◽  
Triple Helix Formation ◽  
In Trans ◽  
Flanking Regions

Abstract Background:Recent studies have drawn attention to transcribed enhancers (trEs) as important regulatory elements of gene expression; however, their characteristics and mechanisms of action remain poorly understood. Results:We profiled the characteristics of trEs and obtained insights into their mechanisms of action. We found that trEs harbor functional duality related to bimodal sequence composition. TrEs are composed of nonoverlapping cores and flanking regions (flanks): cores function as regular enhancers, while flanks transcribe enhancer RNAs (eRNAs) that can potentially regulate the expression of their target genes in trans. Cores are evolutionarily conserved and compact, while flanks are significantly longer. We observed that approximately 25% of eRNAs transcribed from the flanks likely contribute to trans DNA:RNA triple helix formation, while another 10% likely employ classical mechanisms of RNA-based regulation. We found that the majority of human enhancers are not transcribed, and trEs are strikingly different from regular enhancers in their functional characteristics. In addition, we found evidence for trEs exhibiting functional duality in regulatory locus encapsulation (RLE), effectively providing localized control over the spread of gene expression upregulation by trE cores and other locus enhancers. Conclusions:In summary, our results advocate for enhancer transcription being an uncommon mechanism of gene regulation, and the duality of transcribed enhancer function being a product of additive, not overlapping, DNA sequence encryption.

scholarly journals Analysis of (δβ)0 Thalassemia and HPFH Deletions Suggest a Hierarchy of Cis-Acting Elements Regulating Fetal Hemoglobin Gene Expression.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 54-54 ◽  
Author(s):  
Heather L Edward ◽  
Tasha Morrison ◽  
Jacqueline N Milton ◽  
Hong-yuan Luo ◽  
Lance Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Site ◽  
Conflicts Of Interest ◽  
Globin Gene ◽  
Regression Tree ◽  
Fetal Hemoglobin ◽  
Regulatory Elements ◽  
Globin Genes ◽  
Cis Acting ◽  
Cart Analysis

Abstract Hereditary persistence of fetal hemoglobin (HPFH) and (δβ)0 thalassemia are caused by deletions within the β-globin gene (HBB) cluster that remove elements that affect the expression of the γ-globin genes (HBG2 and HBG1, or HBG). These deletions are of different lengths and have different 5’ and 3’ breakpoints. The phenotypes associated with heterozygous carriers of (δβ)0 thalassemia and HPFH deletions are differentiated by levels of 5-15% HbF distributed heterocellularly in the former and 15-30% HbF distributed pancellularly in the latter. We found a novel 588.6 kb deletion that removed both the 3.5 kb fragment 5’ to HBD that is deleted in Corfu β thalassemia and contains a BCL11A binding site, and the known cis-acting elements downstream of HBB. The proband with this deletion had a HbF of 5.4% (Morrison et al, Blood, 2014 abstract 3452). To study the relative importance of 5’ and 3’ regulatory elements in HBG expression we studied 209 cases culled from the literature and from our laboratory where the 3.5 kb element 5’ to HBD and enhancers 3’ to HBB were deleted and HBG remained intact. We used a backwards stepwise regression statistical analysis to determine which deleted elements had the greatest effect on HbF levels. The combination of the deletion of 3.5 kb intergenic region 5’ to HBD, the presence of the HPFH-1 “3D” enhancer juxtaposed to HBG, and the deletion of the 3’ HS1 region accounted for 66.7% of the HbF variation in heterozygotes for HPFH and (δβ)0-thalassemia deletions. The HPFH-1 “3D” enhancer juxtaposed to HBG— the main difference between HPFH-1 and 2 compared with Spanish (δβ)0-thalassemia—was associated with an increase in HbF of 20.78% (p<2e-16) after adjusting for the effects of the other 5’ and 3’ cis-acting elements. The next most significant factor was the deletion of the 3.5 kb fragment 5’ to HBD which resulted in an increase of 10.62% HbF after similar adjustments (p<2e-16); deletion of the 3’ HS1 region accounted for an increase in HbF of 5.25% (p<1.05e-5). The HPFH-3 and HPFH-6 enhancer regions each accounted for a less than 1% increase in HbF and were not significantly associated with HbF in this model. Among 194 individuals where both 5’ and some 3’ elements affecting γ-globin gene expression—excluding the “3D” enhancer—were deleted, HbF was 20±9.3%; in 13 cases where all 3’ enhancers—including the “3D” enhancer—were deleted, HbF was 6.8±3.7% (p=8.9e-07). To determine which combinations of cis-acting elements were associated with high and low HbF levels we performed a classification and regression tree (cART) analysis on HbF. The results of the regression tree (Figure) only included the deletion of the 5’ 3.5 kb fragment region, the presence of the HPFH-1 “3D” enhancer and the deletion of the 3’ HS1 region and were consistent with the results of the backwards selection model. The absence of the 5’ 3.5 kb fragment 5’ to HBD combined with the presence of the HPFH-1 “3D” enhancer was associated with the highest average HbF of 27.02%. The absence of the 3.5 kb fragment 5’ to HBD combined with the absence of the HPFH-1 “3D” enhancer was associated with the lowest average HbF of 6.82%.The 588.6 kb deletion is the largest deletion reported in the HBB cluster that leaves the γ-globin genes intact, and the second to remove both the BCL11A binding site and all known 3’ enhancer elements. By studying deletions in the HBBgene cluster we have further defined the hierarchy of cis-acting elements that modulate HbF levels in adults and suggest a paramount role of the distal “3D” enhancer. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals uORFs: Important Cis-Regulatory Elements in Plants

2020 ◽  
Vol 21 (17) ◽  
pp. 6238
Author(s):  
Ting Zhang ◽  
Anqi Wu ◽  
Yaping Yue ◽  
Yu Zhao
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Translational Regulation ◽  
Regulatory Elements ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Post Translational Modification ◽  
Cis Acting ◽  
Eukaryotic Mrnas

Gene expression is regulated at many levels, including mRNA transcription, translation, and post-translational modification. Compared with transcriptional regulation, mRNA translational control is a more critical step in gene expression and allows for more rapid changes of encoded protein concentrations in cells. Translation is highly regulated by complex interactions between cis-acting elements and trans-acting factors. Initiation is not only the first phase of translation, but also the core of translational regulation, because it limits the rate of protein synthesis. As potent cis-regulatory elements in eukaryotic mRNAs, upstream open reading frames (uORFs) generally inhibit the translation initiation of downstream major ORFs (mORFs) through ribosome stalling. During the past few years, with the development of RNA-seq and ribosome profiling, functional uORFs have been identified and characterized in many organisms. Here, we review uORF identification, uORF classification, and uORF-mediated translation initiation. More importantly, we summarize the translational regulation of uORFs in plant metabolic pathways, morphogenesis, disease resistance, and nutrient absorption, which open up an avenue for precisely modulating the plant growth and development, as well as environmental adaption. Additionally, we also discuss prospective applications of uORFs in plant breeding.

scholarly journals Cis acting variation is common, can propagates across multiple regulatory layers, but is often buffered in developmental programs

2020 ◽  
Author(s):  
Swann Floc’hlay ◽  
Emily Wong ◽  
Bingqing Zhao ◽  
Rebecca R. Viales ◽  
Morgane Thomas-Chollier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcription Factors ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cis Acting ◽  
Dna Mutations ◽  
Allele Specific ◽  
Regulatory Dna ◽  
The Impact

AbstractPrecise patterns of gene expression are driven by interactions between transcription factors, regulatory DNA sequence, and chromatin. How DNA mutations affecting any one of these regulatory ‘layers’ is buffered or propagated to gene expression remains unclear. To address this, we quantified allele-specific changes in chromatin accessibility, histone modifications, and gene expression in F1 embryos generated from eight Drosophila crosses, at three embryonic stages, yielding a comprehensive dataset of 240 samples spanning multiple regulatory layers. Genetic variation in cis-regulatory elements is common, highly heritable, and surprisingly consistent in its effects across embryonic stages. Much of this variation does not propagate to gene expression. When it does, it acts through H3K4me3 or alternatively through chromatin accessibility and H3K27ac. The magnitude and evolutionary impact of mutations is influenced by a genes’ regulatory complexity (i.e. enhancer number), with transcription factors being most robust to cis-acting, and most influenced by trans-acting, variation. Overall, the impact of genetic variation on regulatory phenotypes appears context-dependent even within the constraints of embryogenesis.

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