scholarly journals Positive and negative cis-regulatory elements directing postfertilization maternal mRNA translational control in mouse embryos

2010 ◽  
Vol 299 (4) ◽  
pp. C818-C827 ◽  
Author(s):  
Santhi Potireddy ◽  
Uros Midic ◽  
Cheng-Guang Liang ◽  
Zoran Obradovic ◽  
Keith E. Latham
Keyword(s):  
Secondary Structure ◽  
Translational Control ◽  
Bioinformatics Analysis ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Regulatory Motifs ◽  
Functional Studies ◽  
Maternal Mrna ◽  
Mrna Population

Mechanisms providing for temporally complex patterns of maternal mRNA translation after fertilization are poorly understood. We employed bioinformatics analysis to compare populations of mRNAs enriched specifically on polysomes at the metaphase II (MII) stage oocyte and late one-cell stages and a detailed deletion/truncation series to identify elements that regulate translation. We used the Bag4 3′ untranslated region (UTR) as a model. Bioinformatics analysis revealed one conserved motif, subsequently confirmed by functional studies to be a key translation repressor element. The deletion/truncation studies revealed additional regulatory motifs, most notably a strong translation activator element of <30 nt. Analysis of mRNA secondary structure suggests that secondary structure plays a key role in translation repression. Additional bioinformatics analysis of the regulated mRNA population revealed a diverse collection of regulatory motifs found in small numbers of mRNAs, highlighting a high degree of sequence diversity and combinatorial complexity in the overall control of the maternal mRNA population. We conclude that translational control after fertilization is driven primarily by negative regulatory mechanisms opposing strong translational activators, with stage-specific release of the inhibitory influences to permit recruitment. The combination of bioinformatics analysis and deletion/truncation studies provides the necessary approach for dissecting postfertilization translation regulatory mechanisms.

scholarly journals G-quadruplex located in the 5′UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance

2019 ◽  
Vol 47 (19) ◽  
pp. 10247-10266 ◽  
Author(s):  
Rachel Jodoin ◽  
Julie C Carrier ◽  
Nathalie Rivard ◽  
Martin Bisaillon ◽  
Jean-Pierre Perreault
Keyword(s):  
Colorectal Cancer ◽  
Secondary Structure ◽  
Cancer Cells ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Protein Isoforms ◽  
Initiation Of Translation ◽  
G Quadruplex ◽  
Colorectal Cancer Cells ◽  
Independent Translation

Abstract The anti-apoptotic BAG-1 protein isoforms are known to be overexpressed in colorectal tumors and are considered to be potential therapeutic targets. The isoforms are derived from alternative translation initiations occuring at four in-frame start codons of a single mRNA transcript. Its 5′UTR also contains an internal ribosome entry site (IRES) regulating the cap-independent translation of the transcript. An RNA G-quadruplex (rG4) is located at the 5′end of the BAG-1 5′UTR, upstream of the known cis-regulatory elements. Herein, we observed that the expression of BAG-1 isoforms is post-transcriptionally regulated in colorectal cancer cells and tumors, and that stabilisation of the rG4 by small molecules ligands reduces the expression of endogenous BAG-1 isoforms. We demonstrated a critical role for the rG4 in the control of both cap-dependent and independent translation of the BAG-1 mRNA in colorectal cancer cells. Additionally, we found an upstream ORF that also represses BAG-1 mRNA translation. The structural probing of the complete 5′UTR showed that the rG4 acts as a steric block which controls the initiation of translation at each start codon of the transcript and also maintains the global 5′UTR secondary structure required for IRES-dependent translation.

A story of birth and death: mRNA translation and clearance at the onset of maternal-to-zygotic transition in mammals†

2019 ◽  
Vol 101 (3) ◽  
pp. 579-590 ◽  
Author(s):  
Qian-Qian Sha ◽  
Jue Zhang ◽  
Heng-Yu Fan
Keyword(s):  
Transcriptional Activation ◽  
Translational Control ◽  
De Novo ◽  
Model Organism ◽  
Mrna Translation ◽  
Maternal Mrna ◽  
Maternal To Zygotic Transition ◽  
Maternal Transcripts ◽  
Set Up ◽  
Zygotic Genome

Abstract In mammals, maternal-to-zygotic transition (MZT), or oocyte-to-embryo transition, begins with oocyte meiotic resumption due to the sequential translational activation and destabilization of dormant maternal transcripts stored in the ooplasm. It then continues with the elimination of maternal transcripts during oocyte maturation and fertilization and ends with the full transcriptional activation of the zygotic genome during embryonic development. A hallmark of MZT in mammals is its reliance on translation and the utilization of stored RNAs and proteins, rather than de novo transcription of genes, to sustain meiotic maturation and early development. Impaired maternal mRNA clearance at the onset of MZT prevents zygotic genome activation and causes early arrest of developing embryos. In this review, we discuss recent advances in our knowledge of the mechanisms whereby mRNA translation and degradation are controlled by cytoplasmic polyadenylation and deadenylation which set up the competence of maturing oocyte to accomplish MZT. The emphasis of this review is on the mouse as a model organism for mammals and BTG4 as a licensing factor of MZT under the translational control of the MAPK cascade.

scholarly journals Regulation of Fibronectin EDA Exon Alternative Splicing: Possible Role of RNA Secondary Structure for Enhancer Display

1999 ◽  
Vol 19 (4) ◽  
pp. 2657-2671 ◽  
Author(s):  
Andrés F. Muro ◽  
Massimo Caputi ◽  
Rajalakshmi Pariyarath ◽  
Franco Pagani ◽  
Emanuele Buratti ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Secondary Structure ◽  
Regulatory Region ◽  
Cell Types ◽  
Regulatory Elements ◽  
Base Change ◽  
Significant Feature ◽  
Functional Studies ◽  
Splicing Regulatory Elements

ABSTRACT The fibronectin primary transcript undergoes alternative splicing in three noncoordinated sites: the cassette-type EDA and EDB exons and the more complex IIICS region. We have shown previously that an 81-nucleotide region within the EDA exon is necessary for exon recognition and that this region contains at least two splicing-regulatory elements: a polypurinic enhancer (exonic splicing enhancer [ESE]) and a nearby silencer element (exonic splicing silencer [ESS]). Here, we have analyzed the function of both elements in different cell types. We have mapped the ESS to the nucleotide level, showing that a single base change is sufficient to abolish its function. Testing of the ESE and ESS elements in heterologous exons, individually or as part of the complete EDA regulatory region, showed that only the ESE element is active in different contexts. Functional studies coupled to secondary-structure enzymatic analysis of the EDA exon sequence variants suggest that the role of the ESS element may be exclusively to ensure the proper RNA conformation and raise the possibility that the display of the ESE element in a loop position may represent a significant feature of the exon splicing-regulatory region.

scholarly journals A UV-Induced Mutation in Neurospora That Affects Translational Regulation in Response to Arginine

Genetics ◽  
1996 ◽  
Vol 142 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Michael Freitag ◽  
Nelima Dighde ◽  
Matthew S Sachs
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Fusion Gene ◽  
Mrna Translation ◽  
Small Subunit ◽  
Upstream Open Reading Frame ◽  
Control Mechanisms ◽  
Carbamoyl Phosphate ◽  
Altered Expression ◽  
Reading Frame

The Neurospora crmsu arg-2 gene encodes the small subunit of arginine-specific carbamoyl phosphate synthetase. The levels of arg-2 mRNA and mRNA translation are negatively regulated by arginine. An upstream open reading frame (uORF) in the transcript’s 5′ region has been implicated in arginine-specific control. An arg-2-hph fusion gene encoding hygromycin phosphotransferase conferred arginine-regulated resistance to hygromycin when introduced into N. crassa. We used an arg-2-hph strain to select for UV-induced mutants that grew in the presence of hygromycin and arginine, and we isolated 46 mutants that had either of two phenotypes. One phenotype indicated altered expression of both arg-2-hph and urg-2 genes; the other, altered expression of urg-2-hph but not arg-2. One of the latter mutations, which was genetically closely linked to arg-2-hph, was recovered from the 5′ region of the arg-2-hph gene using PCR. Sequence analyses and transformation experiments revealed a mutation at uORF codon 12 (Asp to Asn) that abrogated negative regulation. Examination of the distribution of ribosomes on arg-2-hph transcripts showed that loss of regulation had a translational component, indicating the uORF sequence was important for Arg-specific translational control. Comparisons with other uORFS suggest common elements in translational control mechanisms.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

The positive regulatory function of the 5'-proximal open reading frames in GCN4 mRNA can be mimicked by heterologous, short coding sequences

1988 ◽  
Vol 8 (9) ◽  
pp. 3827-3836
Author(s):  
N P Williams ◽  
P P Mueller ◽  
A G Hinnebusch
Keyword(s):  
Translational Control ◽  
Normal Growth ◽  
Regulatory Elements ◽  
Growth Conditions ◽  
Open Reading Frames ◽  
Regulatory Function ◽  
Yeast Saccharomyces Cerevisiae ◽  
Reading Frame ◽  
Yeast Genes ◽  
Reading Frames

Translational control of GCN4 expression in the yeast Saccharomyces cerevisiae is mediated by multiple AUG codons present in the leader of GCN4 mRNA, each of which initiates a short open reading frame of only two or three codons. Upstream AUG codons 3 and 4 are required to repress GCN4 expression in normal growth conditions; AUG codons 1 and 2 are needed to overcome this repression in amino acid starvation conditions. We show that the regulatory function of AUG codons 1 and 2 can be qualitatively mimicked by the AUG codons of two heterologous upstream open reading frames (URFs) containing the initiation regions of the yeast genes PGK and TRP1. These AUG codons inhibit GCN4 expression when present singly in the mRNA leader; however, they stimulate GCN4 expression in derepressing conditions when inserted upstream from AUG codons 3 and 4. This finding supports the idea that AUG codons 1 and 2 function in the control mechanism as translation initiation sites and further suggests that suppression of the inhibitory effects of AUG codons 3 and 4 is a general consequence of the translation of URF 1 and 2 sequences upstream. Several observations suggest that AUG codons 3 and 4 are efficient initiation sites; however, these sequences do not act as positive regulatory elements when placed upstream from URF 1. This result suggests that efficient translation is only one of the important properties of the 5' proximal URFs in GCN4 mRNA. We propose that a second property is the ability to permit reinitiation following termination of translation and that URF 1 is optimized for this regulatory function.

scholarly journals Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion

2006 ◽  
Vol 101 (2) ◽  
pp. 576-582 ◽  
Author(s):  
Stephen J. Crozier ◽  
Xueqian Zhang ◽  
Jufang Wang ◽  
Joseph Cheung ◽  
Scot R. Kimball ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Protein Expression ◽  
Signaling Pathways ◽  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Mechanisms ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Mitogen Activated Protein

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.

scholarly journals FINDING NON-CODING RNAs THROUGH GENOME-SCALE CLUSTERING

2009 ◽  
Vol 07 (02) ◽  
pp. 373-388 ◽  
Author(s):  
HUEI-HUN TSENG ◽  
ZASHA WEINBERG ◽  
JEREMY GORE ◽  
RONALD R. BREAKER ◽  
WALTER L. RUZZO
Keyword(s):  
Secondary Structure ◽  
Efficient Method ◽  
Regulatory Mechanisms ◽  
Homology Search ◽  
Substantial Portion ◽  
Primary Sequence ◽  
Clustering Method ◽  
Microbial Genomes ◽  
Non Coding Rnas ◽  
Genome Scale

Non-coding RNAs (ncRNAs) are transcripts that do not code for proteins. Recent findings have shown that RNA-mediated regulatory mechanisms influence a substantial portion of typical microbial genomes. We present an efficient method for finding potential ncRNAs in bacteria by clustering genomic sequences based on homology inferred from both primary sequence and secondary structure. We evaluate our approach using a set of predominantly Firmicutes sequences. Our results showed that, though primary sequence based–homology search was inaccurate for diverged ncRNA sequences, through our clustering method, we were able to infer motifs that recovered nearly all members of most known ncRNA families. Hence, our method shows promise for discovering new families of ncRNA.

scholarly journals Discovery of gene regulatory elements through a new bioinformatics analysis of haploid genetic screens

PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0198463
Author(s):  
Bhaven B. Patel ◽  
Andres M. Lebensohn ◽  
Ganesh V. Pusapati ◽  
Jan E. Carette ◽  
Julia Salzman ◽  
...  
Keyword(s):  
Bioinformatics Analysis ◽  
Regulatory Elements ◽  
Genetic Screens ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle

2000 ◽  
Vol 279 (4) ◽  
pp. E715-E729 ◽  
Author(s):  
O. Jameel Shah ◽  
Joshua C. Anthony ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Translational Control ◽  
Mrna Translation ◽  
Cellular Protein ◽  
Initiation Factor ◽  
Translational Repressor ◽  
Initiation Factors ◽  
Initiation Phase ◽  
Eukaryotic Initiation Factor 4E ◽  
Integration Sites ◽  
A Site

Maintenance of cellular protein stores in skeletal muscle depends on a tightly regulated synthesis-degradation equilibrium that is conditionally modulated under an extensive range of physiological and pathophysiological circumstances. Recent studies have established the initiation phase of mRNA translation as a pivotal site of regulation for global rates of protein synthesis, as well as a site through which the synthesis of specific proteins is controlled. The protein synthetic pathway is exquisitely sensitive to the availability of hormones and nutrients and employs a comprehensive integrative strategy to interpret the information provided by hormonal and nutritional cues. The translational repressor, eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and the 70-kDa ribosomal protein S6 kinase (S6K1) have emerged as important components of this strategy, and together they coordinate the behavior of both eukaryotic initiation factors and the ribosome. This review discusses the role of 4E-BP1 and S6K1 in translational control and outlines the mechanisms through which hormones and nutrients effect changes in mRNA translation through the influence of these translational effectors.

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