MTar: a computational microRNA target prediction architecture for human transcriptome

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) play an essential task in gene regulatory networks by inhibiting the expression of target mRNAs. As their mRNA targets are genes involved in important cell functions, there is a growing interest in identifying the relationship between miRNAs and their target mRNAs. So, there is now a imperative need to develop a computational method by which we can identify the target mRNAs of existing miRNAs. Here, we proposed an efficient machine learning model to unravel the relationship between miRNAs and their target mRNAs.</p> <p>Results</p> <p>We present a novel computational architecture MTar for miRNA target prediction which reports 94.5% sensitivity and 90.5% specificity. We identified 16 positional, thermodynamic and structural parameters from the wet lab proven miRNA:mRNA pairs and MTar makes use of these parameters for miRNA target identification. It incorporates an Artificial Neural Network (ANN) verifier which is trained by wet lab proven microRNA targets. A number of hitherto unknown targets of many miRNA families were located using MTar. The method identifies all three potential miRNA targets (5' seed-only, 5' dominant, and 3' canonical) whereas the existing solutions focus on 5' complementarities alone.</p> <p>Conclusion</p> <p>MTar, an ANN based architecture for identifying functional regulatory miRNA-mRNA interaction using predicted miRNA targets. The area of target prediction has received a new momentum with the function of a thermodynamic model incorporating target accessibility. This model incorporates sixteen structural, thermodynamic and positional features of residues in miRNA: mRNA pairs were employed to select target candidates. So our novel machine learning architecture, MTar is found to be more comprehensive than the existing methods in predicting miRNA targets, especially human transcritome.</p

miRNA-Dependent Translational Repression in the Drosophila Ovary

Background: The Drosophila ovary is a tissue rich in post-transcriptional regulation of gene expression. Many of the regulatory factors are proteins identified via genetic screens. The more recent discovery of microRNAs, which in other animals and tissues appear to regulate translation of a large fraction of all mRNAs, raised the possibility that they too might act during oogenesis. However, there has been no direct demonstration of microRNA-dependent translational repression in the ovary. Methodology/Principal Findings: Here, quantitative analyses of transcript and protein levels of transgenes with or without synthetic miR-312 binding sites show that the binding sites do confer translational repression. This effect is dependent on the ability of the cells to produce microRNAs. By comparison with microRNA-dependent translational repression in other cell types, the regulated mRNAs and the protein factors that mediate repression were expected to be enriched in sponge bodies, subcellular structures with extensive similarities to the P bodies found in other cells. However, no such enrichment was observed. Conclusions/Significance: Our results reveal the variety of post-transcriptional regulatory mechanisms that operate in the Drosophila ovary, and have implications for the mechanisms of miRNA-dependent translational control used in the ovary.This work was supported in part by NIH grant GM54409 and in part by Research Grant No. 1-FY08-445. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Cellular and Molecular Biolog

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use

RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter.

The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high FOXP3 levels and decreased expression of proinflammatory cytokines beta form of pro-IL-1, IL-6, IL-17A, IFN-gamma, and TNF-alpha in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17-characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses

Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases

Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections