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Results for “Translational repression”

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PubMed2004

Altered expression profiles of microRNAs during TPA-induced differentiation of HL-60 cells.

MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that regulate gene expression through translational repression by base-pairing with partially complementary mRNAs. The expression of a set of miRNAs is known to be regulated developmentally and spatially, and is involved in differentiation or cell proliferation in several organisms. However, the expression profiles of human miRNAs during cell differentiation remain largely unknown. In an effort to expand our knowledge of human miRNAs, we investigated miRNAs during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of human leukemia cells (HL-60) into monocyte/macrophage-like cells. Several hundred RNAs ranging from 18 to 26 nucleotides were isolated from HL-60 cells with or without TPA-induction, and subsequently characterized by sequencing, database searching, and expression profiling. By removing non-miRNA sequences, we found three novel and 38 known miRNAs expressed in HL-60 cells. These miRNAs could be further classified into subsets of miRNAs that responded differently following TPA induction, either being up-regulated or down-regulated, suggesting the importance of regulated gene expression via miRNAs in the differentiation of HL-60 cells.

Base Sequence↗

PubMed2005

Polymorphisms in human pre-miRNAs.

MicroRNAs constitute a growing class of non-coding RNAs that are thought to regulate gene expression via translational repression. MicroRNAs are initially transcribed as several hundred-nucleotide pri-miRNAs and are then processed to approximately 60-nucleotide hairpin pre-miRNAs. We hypothesized that polymorphisms in both pre-miRNA and mature microRNA modify various biological processes by influencing the processing and/or target selection of microRNAs. In the present study, we sequenced 173 human pre-miRNA genome regions in 96 subjects and found 10 polymorphisms in the 10 pre-miRNA hairpin regions. Although most of these polymorphisms seem to have no effect on microRNA processing, we identified a C to A polymorphism in the mature miR-30c-2 sequence. This polymorphism may alter target selection and thus exert profound biological effects. To the best of our knowledge, this is the first report of polymorphisms in pre-miRNAs.

Base Sequence↗

PubMed2005

Effects of single amino acid substitutions at the predicted coiled-coil or hydrophobic region on the self-assembly of phi29 replication protein, gp1.

Gp1, the product of one of the essential genes of phi29 replication, is an RNA binding protein and self-associates to form large complexes. Furthermore, gp1 suppresses the synthesis of phi29 DNA polymerase and primer protein in the post-transcriptional process. In this report, we have employed seven variants with single amino acid substitutions to analyze the self-assembly of gp1. Using chemical cross-linking and sedimentation assays, amino acid substitutions within the predicted coiled-coil or hydrophobic region were shown to strongly affect the formation of large complexes, suggesting that these two regions were required for the self-assembly of gp1. The self-association of gp1 was suggested to be necessary for the efficient binding to RNA and the translational repression.

Amino Acid Sequence↗

PubMed2005

Extensive modulation of a set of microRNAs in primary glioblastoma.

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles in animals and plants by repressing translation or cleaving RNA transcripts. The specific modulation of several microRNAs has been recently associated to some forms of human cancer, suggesting that these short molecules may represent a new class of genes involved in oncogenesis. In our study, we examined by microarray the global expression levels of 245 microRNAs in glioblastoma multiforme, the most frequent and malignant of primary brain tumors. The analysis of both glioblastoma tissues and glioblastoma cell lines allowed us to identify a group of microRNAs whose expression is significantly altered in this tumor. The most interesting results came from miR-221, strongly up-regulated in glioblastoma and from a set of brain-enriched miRNAs, miR-128, miR-181a, miR-181b, and miR-181c, which are down-regulated in glioblastoma.

Brain↗

PubMed2006

Cerebral ischemia induces neuronal expression of novel VL30 mouse retrotransposons bound to polyribosomes.

Mammalian genomes are burdened with a large heterogeneous group of endogenous replication defective retroviruses (retrotransposons). Previously, we identified a transcript resembling a virus-like 30S (VL30) retrotransposon increasing in mouse brain following transient cerebral ischemia. Paradoxically, this non-coding RNA was found bound to polyribosomes. Further analysis revealed that multiple retrotransposon species (BVL-1-like and mVL30-1-like) were bound to polyribosomes and induced by ischemia. These VL30 transcripts remained associated with polyribosomes in the presence of 0.5 M KCl, indicating that VL30 mRNA was tightly associated with ribosomal subunits. Furthermore, the profile of BVL-1 distribution on polyribosomal profiles was distinct from those of translated and translationally repressed mRNA. Consistent with expectations, 5.0 kb VL30 transcripts were detected in ischemic brain with a temporal pattern of expression that was distinct from c-fos. Expression of VL30 was localized in neurons using a combination of in situ hybridization and immunocytochemistry. 3'-RACE-PCR experiments yielded two unique sequences (VL30x-1 and VL30x-2) that were homologous to known VL30 genes. Phylogenetic analysis of VL30 promoter sequence (U3 region) resulted in the identification of two large VL30 subgroups. VL30x-1 and VL30x-2 were closely related and classified in a group that was distinct from the well-characterized VL30 genes BVL-1 and mVL30-1. The promoter regions of VL30x-1 and VL30x-2 did not possess the consensus sequences for either hypoxia or anoxia response elements, suggesting an alternative mechanism for induction. This is the first report that demonstrates ischemia-induced, neuronal expression of unique VL30 retrotransposons in mouse brain.

Animals↗

PubMed2004

Nonsense-mediated mRNA decay: terminating erroneous gene expression.

Nonsense-mediated mRNA decay is a surveillance pathway that reduces errors in gene expression by eliminating aberrant mRNAs that encode incomplete polypeptides. Recent experiments suggest a working model whereby premature and normal translation termination events are distinct as a consequence of the spatial relationship between the termination codon and mRNA binding proteins, a relationship partially established by nuclear pre-mRNA processing. Aberrant termination then leads to both translational repression and an increased susceptibility of the mRNA to multiple ribonucleases.

3' Untranslated Regions↗

PubMed2005

Computational detection of microRNAs targeting transcription factor genes in Arabidopsis thaliana.

MicroRNAs, an abundant class of tiny non-coding RNAs, have emerged as negative regulators for translational repression or cleavage of target mRNAs by the manner of complementary base paring in plants and animals. Recent studies have demonstrated that many known microRNAs have a remarkable propensity to target genes involved in development, particularly those of transcription factor genes. Therefore, an overall detection of Arabidopsis thaliana microRNAs targeting transcription factor genes will enhance greatly our understanding of microRNA biological functions in plant development. By searching short complementary sequences between transcription factor open-reading frames and intergenic region sequences, and considering RNA secondary structures and the sequence conversation between the genomes of Arabidopsis and Oryza sativa, we detected 96 candidate Arabidopsis microRNAs. These candidate microRNAs were predicted to target 102 transcription factor genes that are classified as 28 transcription factor gene families, particularly those of DNA-binding transcription factor families, which imply that microRNAs might be involved in complex transcriptional regulatory networks for specifying individual cell types in plant development.

Arabidopsis↗

PubMed2006

Computational identification of microRNAs and their targets.

MicroRNAs (miRNAs) are one class of newly identified riboregulators of gene expression in many eukaryotic organisms. They play important roles in multiple biological and metabolic processes, including developmental timing, signal transduction, cell maintenance and differentiation, diseases and cancers. miRNAs regulate gene expression at the posttranscriptional level by directly cleaving targeted mRNAs or repressing translation. Although the founding members of miRNAs were discovered by genetic screening approaches, experimental approaches were limited by their low efficiency, time consuming, and high cost. As an alternative, computational approaches were developed. Computational approaches for identifying miRNAs are based on the following major characteristics of miRNAs: hairpin-shaped secondary structures, high conservation for some miRNAs, and high minimal folding free energy index (MFEI). Computational approaches also play an important role in identifying miRNA targets. A majority of known miRNAs and their targets were identified by computational approaches. Several web-based or non-web-based computer software programs are publicly available for predicting miRNAs and their targets.

Animals↗

PubMed2005

Role reversal: the regulation of neuronal gene expression by microRNAs.

In a similar fashion to transcription factors, non-coding RNAs can be essential regulators of gene expression. The largest class of non-coding RNAs is the microRNAs. These approximately 22 nt double-stranded RNA molecules can repress translation or target mRNA degradation. There has been a surge of research in the past year stimulated by the recent availability of specialized techniques, both in vitro and in silico, for predicting and characterizing microRNAs. The accumulating evidence suggests that microRNAs are ubiquitous regulators of gene expression during development. The combined actions of microRNAs and transcription factors are able to tune the expression of proteins on a global level in a manner that cannot be achieved by transcription factors alone.

Animals↗

PubMed2005

RNase III-mediated silencing of a glucose-dependent repressor in yeast.

Members of the RNase III family are found in all species examined with the exception of archaebacteria, where the functions of RNase III are carried out by the bulge-helix-bulge nuclease (BHB). In bacteria, RNase III contributes to the processing of many noncoding RNAs and directly cleaves several cellular and phage mRNAs. In eukaryotes, orthologs of RNase III participate in the biogenesis of many miRNAs and siRNAs, and this biogenesis initiates the degradation or translational repression of several mRNAs. However, the capacity of eukaryotic RNase IIIs to regulate gene expression by directly cleaving within the coding sequence of mRNAs remains speculative. Here we show that Rnt1p, a member of the RNase III family, selectively inhibits gene expression in baker's yeast by directly cleaving a stem-loop structure within the mRNA coding sequence. Analysis of mRNA expression upon the deletion of Rnt1p revealed an upregulation of the glucose-dependent repressor Mig2p. Mig2p mRNA became more stable upon the deletion of Rnt1p and resisted glucose-dependent degradation. In vitro, Rnt1p cleaved Mig2p mRNA and a silent mutation that disrupts Rnt1p signals blocked Mig2p mRNA degradation. These observations reveal a new RNase III-dependent mechanism of eukaryotic mRNA degradation.

Blotting, Northern↗

PubMed2005

Gene circuitry controlling a stem cell niche.

Many stem cell populations interact with stromal cells via signaling pathways, and understanding these interactions is key for understanding stem cell biology. In Drosophila, germline stem cell (GSC) maintenance requires regulation of several genes, including dpp, piwi, pumilio, and bam. GSCs also maintain continuous contact with cap cells that probably secrete the signaling ligands necessary for controlling expression of these genes. For example, dpp signaling acts by silencing transcription of the differentiation factor, bam, in GSCs. Despite numerous studies, it is not clear what roles piwi, primarily a cap cell factor, and pumilio, a germ cell factor, play in maintaining GSC function. With molecular and genetic experiments, we show that piwi maintains GSCs by silencing bam. In contrast, pumilio is not required for bam silencing, indicating that pumilio maintains GSC fate by a mechanism not dependent on bam transcription. Surprisingly, we find that germ cells can differentiate without bam if they also lack pumilio. These findings suggest a molecular pathway for GSC maintenance. dpp- and piwi-dependent signaling act synergistically in GSCs to silence bam, whereas pumilio represses translation of differentiation-promoting mRNAs. In cystoblasts, accumulating Bam protein antagonizes pumilio, permitting the translation of cystoblast-promoting transcripts.

Animals↗

PubMed2006

Conserved ribonuclease, Eri1, negatively regulates heterochromatin assembly in fission yeast.

RNA interference (RNAi) is a conserved silencing mechanism that has widespread roles in RNA degradation, translational repression, and the epigenetic control of chromatin structure [1]. In fission yeast, heterochromatin assembly requires RNAi machinery and is initiated by small interference RNAs (siRNAs) derived from heterochromatic regions and by the RNA-induced transcriptional silencing (RITS) complex [2-7]. Although recent studies have been successful in uncovering the functions of effector complexes in the RNAi pathway [4, 5, 8-10], exactly how heterochromatic siRNAs are processed and function in assembling heterochromatin remains unclear. In this study we focused on a conserved ribonuclease, Eri1, which was originally identified as a negative regulator of RNAi in C. elegans [11], and show the importance of the Eri1 protein in RNAi-mediated heterochromatin assembly in fission yeast. Eri1 specifically degrades double-stranded siRNAs through two functional domains and represses the accumulation of cellular siRNAs in vivo. Deletion of eri1(+) causes an increase in siRNAs associated with the RITS complex and enhances heterochromatic silencing, which is accompanied by increased levels of histone H3-K9 methylation and the Swi6 protein. Our findings suggest that the fission yeast Eri1 controls the accumulation of heterochromatic siRNAs and negatively regulates the RNAi-mediated heterochromatin assembly.

Amino Acid Sequence↗

PubMed2006

Differential regulation of germline mRNAs in soma and germ cells by zebrafish miR-430.

Early in development, primordial germ cells (PGCs) are set aside from somatic cells and acquire a unique gene-expression program . The mechanisms underlying germline-specific gene expression are largely unknown. Nanos expression is required during germline development and is posttranscriptionally restricted to PGCs . Here we report that the microRNA miR-430 targets the 3' untranslated region (UTR) of nanos1 during zebrafish embryogenesis. A miR-430 target site within the nanos1 3' UTR reduces poly(A) tail length, mRNA stability, and translation. Repression is disrupted in maternal-zygotic dicer mutants (MZdicer), which lack mature miRNAs , and is restored by injection of processed miR-430. Although miR-430 represses other genes equally in germline and soma, specific regions in the nanos1 3' UTR compensate for microRNA-mediated repression in PGCs and allow germline-specific expression. We show that the 3' UTR of an additional PGC-specific gene, TDRD7, is also targeted by miR-430. These results indicate that miR-430 targets the 3' UTRs of germline genes and suggest that differential susceptibility to microRNAs contributes to tissue-specific gene expression.

3' Untranslated Regions↗

PubMed2005

Specific effects of microRNAs on the plant transcriptome.

Most plant microRNAs (miRNAs) have perfect or near-perfect complementarity with their targets. This is consistent with their primary mode of action being cleavage of target mRNAs, similar to that induced by perfectly complementary small interfering RNAs (siRNAs). However, there are natural targets with up to five mismatches. Furthermore, artificial siRNAs can have substantial effects on so-called off-targets, to which they have only limited complementarity. By analyzing the transcriptome of plants overexpressing different miRNAs, we have deduced a set of empirical parameters for target recognition. Compared to artificial siRNAs, authentic plant miRNAs appear to have much higher specificity, which may reflect their coevolution with the remainder of the transcriptome. We also demonstrate that miR172, previously thought to act primarily by translational repression, can efficiently guide mRNA cleavage, although the effects on steady-state levels of target transcripts are obscured by strong feedback regulation. This finding unifies the view of plant miRNA action.

Base Pairing↗

PubMed2007

SMAUG is a major regulator of maternal mRNA destabilization in Drosophila and its translation is activated by the PAN GU kinase.

In animals, egg activation triggers a cascade of posttranscriptional events that act on maternally synthesized RNAs. We show that, in Drosophila, the PAN GU (PNG) kinase sits near the top of this cascade, triggering translation of SMAUG (SMG), a multifunctional posttranscriptional regulator conserved from yeast to humans. Although PNG is required for cytoplasmic polyadenylation of smg mRNA, it regulates translation via mechanisms that are independent of its effects on the poly(A) tail. Analyses of mutants suggest that PNG relieves translational repression by PUMILIO (PUM) and one or more additional factors, which act in parallel through the smg mRNA's 3' untranslated region (UTR). Microarray-based gene expression profiling shows that SMG is a major regulator of maternal transcript destabilization. SMG-dependent mRNAs are enriched for gene ontology annotations for function in the cell cycle, suggesting a possible causal relationship between failure to eliminate these transcripts and the cell cycle defects in smg mutants.

3' Untranslated Regions↗

PubMed2005

Uncovering RNAi mechanisms in plants: biochemistry enters the foray.

In plants, the RNA interference (RNAi) machinery responds to a variety of triggers including viral infection, transgenes, repeated elements and transposons. All of these triggers lead to silencing outcomes ranging from mRNA degradation to translational repression to chromatin remodeling. Thus, plants offer us a potentially unique opportunity to understand the full range of RNAi effector mechanisms. In this review, we discuss the recent developments in our understanding of plant RNAi mechanisms from a biochemical perspective.

Animals↗

PubMed2006

Mismatched siRNAs downregulate mRNAs as a function of target site location.

In mammalian cells, RNA interference can be mediated by synthetic duplex RNAs, termed small interfering RNAs (siRNAs), which assist in cleaving completely complementary mRNA transcripts. MicroRNAs (miRNAs) are endogenous small RNAs that assist in translationally repressing mRNAs with regions of partial complementarity, but may also reduce transcript levels. Since miRNAs predominantly interact with the 3' UTRs of transcripts, we sought to ask if mismatched siRNAs mimicking miRNAs affect cognate mRNA levels as a function of target site location. We find that mismatched siRNAs targeting the 3' UTRs of two endogenous transcripts yield a greater reduction in mRNA levels than those targeting the coding region. Our findings demonstrate the importance of target site location within endogenous mRNAs for small RNAs associated with RNAi.

ATP-Binding Cassette Transporters↗

PubMed2006

Mapping contacts of the S12-S7 intercistronic region of str operon mRNA with ribosomal protein S7 of E. coli.

In E. coli, S7 initiates 30S ribosome assembly by binding to 16S rRNA. It also regulates translation of the S12 and S7 cistrons of the 'streptomycin' operon transcript by binding to the S12-S7 intercistronic region. Here, we describe the contacts of N-terminally His(6)-tagged S7 with this region as mapped by UV-induced cross-linking. The cross-links are located at U(-34), U(-35), quite distant from the start codons of the two cistrons. In order to explain the mechanism of translational repression of S12-S7, we consider a possible conformational rearrangement of the intercistronic RNA structure induced by S7 binding.

Base Sequence↗