9 research outputs found
Regulation of host gene expression by HIV-1 TAR microRNAs
Background:
The transactivating response (TAR) element of human immunodeficiency virus type 1 (HIV-1) is the source of two functional microRNAs (miRNAs), miR-TAR-5p and miR-TAR-3p. The objective of this study was to characterize the post-transcriptional regulation of host messenger RNAs (mRNAs) relevant to HIV-1 pathogenesis by HIV-1 TAR miRNAs.
Results:
We demonstrated that TAR miRNAs derived from HIV-1 can incorporate into host effector Argonaute protein complexes, which is required if these miRNAs are to regulate host mRNA expression. Bioinformatic predictions and reporter gene activity assays identified regulatory elements complementary and responsive to miR-TAR-5p and miR-TAR-3p in the 3ā untranslated region (UTR) of several candidate genes involved in apoptosis and cell survival. These include Caspase 8, Aiolos, Ikaros and Nucleophosmin (NPM)/B23. Analyses of Jurkat cells that stably expressed HIV-1 TAR or contained a full-length latent HIV provirus suggested that HIV-1 TAR miRNAs could regulate the expression of genes in T cells that affect the balance between apoptosis and cell survival.
Conclusions:
HIV-1 TAR miRNAs may contribute to the replication cycle and pathogenesis of HIV-1, by regulating host genes involved in the intricate balance between apoptosis and infected cell, to induce conditions that promote HIV-1 propagation and survival
Ćtude de la rĆ©gulation gĆ©nique post-transcriptionnelle impliquant Dcr1 chez Schizosaccharomyces pombe
Regulatory RNAs : future perspectives in diagnosis, prognosis, and individualized therapy
With potentially up to 1000 microRNAs (miRNAs) present in the human genome, altogether regulating the expression of thousands of genes, one can anticipate that miRNAs will play a significant role in health and disease. Deregulated protein expression induced by a dysfunctional miRNA-based regulatory system is thus expected to lead to the development of serious, if not lethal, genetic diseases. A relationship among miRNAs, Dicer, and cancer has recently been suggested. Further investigations will help establish specific causal links between dysfunctional miRNAs and diseases. miRNAs of foreign origin, e.g., viruses, may also be used as specific markers of viral infections. In these cases, miRNA expression profiles could represent a powerful diagnostic tool. Regulatory RNAs may also have therapeutic applications, by which disease-causing genes or viral miRNAs could be neutralized, or functional miRNAs be restored. Will bedside miRNA expression profiling eventually assist physicians in providing patients with accurate diagnosis, personalized therapy, and treatment outcome
Involvement of Dcr1 in post-transcriptional regulation of gene expression in Schizosaccharomyces pombe.
The ribonuclease III Dicer (Dcr1) has been shown to be required for chromosome segregation and
gene silencing in Schizosaccharomyces pombe. These effects are thought to be transcriptional,
mediated by formation and maintenance of heterochromatin, and guided by small RNAs derived
from Dcr1 along a process known as RNA interference. In order to get further insights into the
gene regulatory role of Dcr1, we performed comparative analyses of dcr1 knockout and wild-type
fission yeast strains. Analysis of part of the soluble proteomes identified eight cellular proteins
whose expression is under Dcr1 control, three of which are integral constituents of the glycolysis
pathway. Further correlations with their respective mRNA transcript levels are compatible with
the existence of a post-transcriptional gene regulatory mechanism involving Dcr1 or a Dcr1
complex. Experiments designed to identify components of Dcr1 complexes unveiled two novel
Dcr1 interactors, namely the zinc finger protein Byr3 and the ribosomal protein L12. Consistently
enriched in Dcr1 immune complexes, Byr3 and L12 may link Dcr1 to the transcriptional and
translational machineries, respectively, and contribute to post-transcriptional gene regulation in
fission yeast
MicroRNAs in Gene Regulation: When the Smallest Governs It All
Encoded by the genome of most eukaryotes examined so far,
microRNAs (miRNAs) are small ~21-nucleotide (nt) noncoding
RNAs (ncRNAs) derived from a biosynthetic cascade involving
sequential processing steps executed by the ribonucleases
(RNases) III Drosha and Dicer. Following their recent
identification, miRNAs have rapidly taken the center stage as key
regulators of gene expression. In this review, we will summarize
our current knowledge of the miRNA biosynthetic pathway and its
protein components, as well as the processes it regulates via
miRNAs, which are known to exert a variety of biological functions
in eukaryotes. Although the relative importance of miRNAs remains
to be fully appreciated, deregulated protein expression resulting
from either dysfunctional miRNA biogenesis or abnormal miRNA-based
gene regulation may represent a key etiologic factor in several,
as yet unidentified, diseases. Hence is our need to better understand
the complexity of the basic mechanisms underlying miRNA biogenesis
and function
Dicer-Derived MicroRNAs Are Utilized by the Fragile X Mental Retardation Protein for Assembly on Target RNAs
In mammalian cells, fragile X mental retardation protein (FMRP)
has been reported to be part of a microRNA (miRNA)-containing
effector ribonucleoprotien (RNP) complex believed to mediate
translational control of specific mRNAs. Here, using recombinant
proteins, we demonstrate that human FMRP can act as a miRNA
acceptor protein for the ribonuclease Dicer and facilitate the
assembly of miRNAs on specific target RNA sequences. The miRNA
assembler property of FMRP was abrogated upon deletion of its
single-stranded (ss) RNA binding K-homology domains. The
requirement of FMRP for efficient RNA interference (RNAi) in vivo
was unveiled by reporter gene silencing assays using various small
RNA inducers, which also supports its involvement in an ss small
interfering RNA (siRNA)-containing RNP (siRNP) effector complex in
mammalian cells. Our results define a possible role for FMRP in
RNA silencing and may provide further insight into the molecular
defects in patients with the fragile X syndrome