Silence - Latest Articles

microRNA as a new immune-regulatory agent in breast milk

Nobuyoshi Kosaka — 2010-03-01T00:00:00Z

Background: Breast milk is a complex liquid that provides nutrition to the infant and facilitates the maturation of the infant's immune system. Recent studies indicated that microRNA (miRNA) exists in human body fluid. Because miRNAs are known to regulate various immune systems, we hypothesized that human breast milk contains miRNAs that may be important for the development of the infant's immune system.FindingsWe profiled miRNA expression in human breast milk and detected high expression levels of immune-related miRNAs in the first 6 months of lactation. Furthermore, these miRNA molecules are stable even in very acidic conditions, indicating that breast milk allows dietary intake of miRNAs by infants. Conclusions: Our findings provide new insight into how breast milk can modulate the development of the infant's immune system. This study suggests the transfer of genetic material as miRNA from human to human occurs by means other than through sexual reproduction.

Development of the human cancer microRNA network

Sanghamitra Bandyopadhyay — 2010-02-02T00:00:00Z

Background: MicroRNAs are a class of small noncoding RNAs that are abnormally expressed in different cancer cells. Molecular signature of miRNAs in different malignancies suggests that these are not only actively involved in the pathogenesis of human cancer but also have a significant role in patients survival. The differential expression patterns of specific miRNAs in a specific cancer tissue type have been reported in hundreds of research articles. However limited attempt has been made to collate this multitude of information and obtain a global perspective of miRNA dysregulation in multiple cancer types. Results: In this article a cancer-miRNA network is developed by mining the literature of experimentally verified cancer-miRNA relationships. This network throws up several new and interesting biological insights which were not evident in individual experiments, but become evident when studied in the global perspective. From the network a number of cancer-miRNA modules have been identified based on a computational approach to mine associations between cancer types and miRNAs. The modules that are generated based on these association are found to have a number of common predicted target onco/tumor suppressor genes. This suggests a combinatorial effect of the module associated miRNAs on target gene regulation in selective cancer tissues or cell lines. Moreover, neighboring miRNAs (group of miRNAs that are located within 50 kb of genomic location) of these modules show similar dysregulation patterns suggesting common regulatory pathway. Besides this, neighboring miRNAs may also show a similar dysregulation patterns (differentially coexpressed) in the cancer tissues. In this study, we found that in 67% of the cancer types have at least two neighboring miRNAs showing downregulation which is statistically significant (P < 10-7, Randomization test). A similar result is obtained for the neighboring miRNAs showing upregulation in specific cancer type. These results elucidate the fact that the neighboring miRNAs might be differentially coexpressed in cancer tissues as that of the normal tissue types. Additionally, cancer-miRNA network efficiently detect hub miRNAs dysregulated in many cancer types and identify cancer specific miRNAs. Depending on the expression patterns, it is possible to identify those hubs that have strong oncogenic or tumor suppressor characteristics. Conclusions: Limited work has been done towards revealing the fact that a number of miRNAs can control commonly altered regulatory pathways. However, this becomes immediately evident by accompanying the analysis of cancer-miRNA relationships in the proposed network model. These raise many unaddressed issues in miRNA research that have never been reported previously. These observations are expected to have an intense implication in cancer and may be useful for further research.

Expression patterns of intronic microRNAs in Caenorhabditis elegans

Meltem Isik — 2010-02-01T00:00:00Z

Background: MicroRNAs (miRNA) are an abundant and ubiquitous class of small RNAs that play prominent roles in gene regulation. A significant fraction of miRNA genes reside in the introns of the host genes in the same orientation and are thought to be co-processed from the host gene mRNAs and thus depend on the host gene promoter for their expression. However, several lines of evidence for independent expression of intronic miRNAs exist in the literature but the extent of this independence remains unclear. Results: We performed a systematic analysis of genomic regions surrounding intronic miRNAs in the nematode Caenorhabditis elegans and found that, in many cases, there are extended intronic sequences immediately upstream of the miRNAs that are well-conserved between the nematodes. We have generated transcriptional green fluorescent protein reporter fusions in transgenic C. elegans lines and demonstrated that, in all seven investigated cases, the conserved sequences show promoter properties and produce specific expression patterns that are different from the host gene expression patterns. The observed expression patterns are corroborated by the published small RNA sequencing data. Conclusions: Our analysis reveals that the number of intronic miRNAs that do not rely on their host genes for expression is substantially higher than previously appreciated. At least one-third of the same-strand intronic miRNAs in C. elegans posses their own promoters and, thus, could be transcribed independently from their host genes. These findings provide a new insight into the regulation of miRNA genes and will be useful for the analysis of interactions between miRNAs and their host genes.

Aptamer-targeted cell-specific RNA interference

Jiehua Zhou — 2010-02-01T00:00:00Z

This potent ability of small interfering (si)RNAs to inhibit the expression of complementary RNA transcripts is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of siRNAs into specific cell populations is still the principal challenge in the clinical development of RNAi therapeutics. With the increasing enthusiasm for developing targeted delivery vehicles, nucleic acid-based aptamers targeting cell surface proteins are being explored as promising delivery vehicles to target a distinct disease or tissue in a cell-type-specific manner. The aptamer-based delivery of siRNAs can often enhance the therapeutic efficacy and reduce the unwanted off-target effects of siRNAs. In particular, for RNA interference-based therapeutics, aptamers represent an efficient agent for cell type-specific, systemic delivery of these oligonucleotides. In this review, we summarize recent attractive developments in creatively using cell-internalizing aptamers to deliver siRNAs to target cells. The optimization and improvement of aptamer-targeted siRNAs for clinical translation are further highlighted.

How to slice: snapshots of Argonaute in action

James Parker — 2010-01-12T00:00:00Z

Argonaute is the principal protein component of the mechanisms of RNA silencing, providing anchor sites for the small guide RNA strand and the 'slicer' activity for cleavage of target mRNAs or short passenger RNA strands. Argonaute is the core constituent of the silencing effector complexes RISC (RNA-induced silencing complex) and the RITS complex (RNA-induced initiation of transcriptional gene silencing complex), interacting directly or indirectly with Dicer proteins, R2D2/Loquacious/TRBP and GW182 family proteins in the former, and Chp1 and Tas3 in the latter. In a breakthrough series of papers, Patel et al. provide a set of 'molecular snapshots' of the catalytic cycle of Argonaute, exploiting mismatches and mutants to capture and visualize by X-ray crystallography Argonaute from Thermus thermophilus with guide and target strands at various stages of the silencing process. The structural studies, coupled to structure-directed biochemical analysis, together with other thermodynamic and kinetic studies, provide insights into Argonaute with implications for the mechanisms of RNA silencing in eukaryotes.

Solution structure of the Drosha double-stranded RNA-binding domain

Geoffrey Mueller — 2010-01-12T00:00:00Z

Background: Drosha is a nuclear RNase III enzyme that initiates processing of regulatory microRNA. Together with partner protein DiGeorge syndrome critical region 8 (DGCR8), it forms the Microprocessor complex, which cleaves precursor transcripts called primary microRNA to produce hairpin precursor microRNA. In addition to two RNase III catalytic domains, Drosha contains a C-terminal double-stranded RNA-binding domain (dsRBD). To gain insight into the function of this domain, we determined the nuclear magnetic resonance (NMR) solution structure. Results: We report here the solution structure of the dsRBD from Drosha (Drosha-dsRBD). The αβββα fold is similar to other dsRBD structures. A unique extended loop distinguishes this domain from other dsRBDs of known structure. Conclusions: Despite uncertainties about RNA-binding properties of the Drosha-dsRBD, its structure suggests it retains RNA-binding features. We propose that this domain may contribute to substrate recognition in the Drosha-DGCR8 Microprocessor complex.

Welcome to Silence

David Baulcombe — 2010-01-12T00:00:00Z

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