Non-coding RNA Pathways Research Articles

Advances, nuances, and potential pitfalls when exploiting the therapeutic potential of RNA interference.

The discovery of RNA interference (RNAi) holds the potential to alter the paradigm of medical therapeutics. With the ability to selectively silence the function of a gene, RNAi not only provides an indispensable research tool for determining the function of a gene, but also offers potential for the development of novel therapeutics that will inhibit specific genes involved in disease. New concepts in therapeutics have been uncovered through the study of RNAi. Nuances have emerged. For instance, global RNAi pathways can be affected by somatic mutations in cancer and cellular stress, such as hypoxia. Also, viral gene therapy can have unexpected effects on endogenous short noncoding RNA pathways. Therefore, it is important to understand where RNAi therapeutics enter the processing pathways. We highlight the evolving use of RNAi as a new class of therapeutics, such as for amyloidosis, and address some of the anticipated challenges associated with its clinical application.

Programmed Genome Rearrangements in the Ciliate Oxytricha.

The ciliate Oxytricha is a microbial eukaryote with two genomes, one of which experiences extensive genome remodeling during development. Each round of conjugation initiates a cascade of events that construct a transcriptionally active somatic genome from a scrambled germline genome, with considerable help from both long and small noncoding RNAs. This process of genome remodeling entails massive DNA deletion and reshuffling of remaining DNA segments to form functional genes from their interrupted and scrambled germline precursors. The use of Oxytricha as a model system provides an opportunity to study an exaggerated form of programmed genome rearrangement. Furthermore, studying the mechanisms that maintain nuclear dimorphism and mediate genome rearrangement has demonstrated a surprising plasticity and diversity of noncoding RNA pathways, with new roles that go beyond conventional gene silencing. Another aspect of ciliate genetics is their unorthodox patterns of RNA-mediated, epigenetic inheritance that rival Mendelian inheritance. This review takes the reader through the key experiments in a model eukaryote that led to fundamental discoveries in RNA biology and pushes the biological limits of DNA processing.

The roles of retinoic acid and retinoic acid receptors in inducing epigenetic changes.

Epigenetics is "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being" as defined by Conrad Waddington in 1942 in a discussion of the mechanisms of cell differentiation. More than seven decades later we know that these mechanisms include histone tail post-translational modifications, DNA methylation, ATP-dependent chromatin remodeling, and non-coding RNA pathways. Epigenetic modifications are powerful drugs targets, and combined targeting of multiple pathways is expected to significantly advance cancer therapy.

Small Noncoding RNAs in the Germline

Small noncoding RNAs have emerged as potent regulators of gene expression, especially in the germline. We review the biogenesis and regulatory function of three major small noncoding RNA pathways in the germline: The small interfering RNA (siRNA) pathway that leads to the degradation of target mRNAs, the microRNA (miRNA) pathway that mostly represses the translation of target mRNAs, and the newly discovered Piwi-interacting RNA (piRNA) pathway that appears to have diverse functions in epigenetic programming, transposon silencing, and the regulation of mRNA translation and stability. The siRNA and miRNA pathways are present in the germline as well as many somatic tissues, whereas the piRNA pathway is predominantly confined to the germline. Investigation of the three small RNA pathways has started to reveal a new dimension of gene regulation with defining roles in germline specification and development.

Evolution of RNA-Binding Proteins in Animals: Insights from Genome-Wide Analysis in the Sponge Amphimedon queenslandica

RNA-binding proteins (RBPs) are key players in various biological processes, most notably regulation of gene expression at the posttranscriptional level. Although many RBPs have been carefully studied in model organisms, very few studies have addressed the evolution of these proteins at the scale of the animal kingdom. We identified a large set of putative RBPs encoded by the genome of the demosponge Amphimedon queenslandica, a species representing a basal animal lineage. We compared the Amphimedon RBPs with those encoded by the genomes of two bilaterians (human and Drosophila), representatives of two other basal metazoan lineages (a placozoan and a cnidarian), a choanoflagellate (probable sister group of animals), and two fungi. We established the evolutionary history of 32 families of RBPs and found that most of the diversity of RBPs present in contemporary metazoans, including humans, was already established in the last common ancestor (LCA) of animals. This includes RBPs known to be involved in key processes in bilaterians, such as development, stem and/or germ cells properties, and noncoding RNA pathways. From this analysis, we infer that a complex toolkit of RBPs was present in the LCA of animals and that it has been recruited to perform new functions during early animal evolution, in particular in relation to the acquisition of multicellularity.