Wednesday, October 10, 2007

MiRNA learning note (1)

MicroRNA-143 and -145 in colon cancer. [DNA Cell Biol. 2007]
MicroRNAs (miRNAs) are endogenous, small non-coding RNAs (20-22 nucleotides) that negatively regulate gene expression at the translational level by base pairing to the 3' untranslated region of target messenger RNAs.
"It is predicted that 30% of protein-encoding genes are regulated by miRNAs."

Principles of microRNA regulation of a human cellular signaling network : Article : Molecular Systems Biology: "By analyzing the interactions between miRNAs and a human cellular signaling network, we found that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands."

Global analysis of microRNA target gene expression reveals that miRNA targets are lower expressed in mature mouse and Drosophila tissues than in the embryos -- Yu et al. 35 (1): 152 -- Nucle: "We found that the expression levels of miRNA targets are lower in all mouse and Drosophila tissues than in the embryos. We also found miRNAs more preferentially target ubiquitously expressed genes than tissue-specifically expressed genes. These results support the current suggestion that miRNAs are likely to be largely involved in embryo development and maintaining of tissue identity."

NB: This kind of expression survey at different ontogenetic stages is very important, because it covers a blind spot in analyses that depend on functional categories. For example GO analyses include categories for "development", but as Yu and colleagues point out, many genes change in expression during development that are not part of the "developmental" categories. (from John Hawks's weblog)

Identification of specific sequence motifs in the ...[Comput Biol Chem. 2007] - PubMed Result: "The significantly reduced frequency of occurrence of all 20 motifs in the regions 2000 bp upstream of 23,570 human RefSeq genes demonstrated that these motifs were specific to the upstream miRNA sequences. The most frequently observed motif M1 (GTGCTTMTAGTGCAG), with a MEME E-value of 3.8e-57 was distributed within 500 bp upstream of stem-loop sequences and was also miRNA-specific."

Regulatory circuit of human microRNA biogenesis. [PLoS Comput Biol. 2007] - PubMed Result: "Newly identified regulatory motifs occur frequently and in multiple copies upstream of miRNAs. The motifs are highly enriched in G and C nucleotides, in comparison with the nucleotide composition of miRNA upstream sequences. Although the motifs were predicted using sequences that are upstream of miRNAs, we find that 99% of the top-predicted motifs preferentially occur within the first 500 nucleotides upstream of the transcription start sites of protein-coding genes; the observed preference in location underscores the validity and importance of the motifs identified in this study. Our study also raises the possibility that a considerable number of well-characterized, disease-associated transcription factors (TFs) of protein-coding genes contribute to the abnormal miRNA expression in diseases such as cancer."

"Further analysis of predicted miRNA-protein interactions lead us to hypothesize that TFs that include c-Myb, NF-Y, Sp-1, MTF-1, and AP-2alpha are master-regulators of miRNA expression."

Spatial regulation of microRNA gene expression in the Drosophila embryo: "we investigate the possibility that localized expression is mediated by tissue-specific enhancers, comparable to those seen for protein-coding genes."

mir-309–6 polycistron (8-miR) : An 800-bp 5′ enhancer was identified that recapitulates this complex pattern when attached to a RNA polymerase II core promoter fused to a lacZ-reporter gene.

mir-1 gene: a mesoderm-specific enhancer located ≈5 kb 5′ of the miR-1 transcription unit.

Evidence is presented that the 8-miR enhancer is regulated by the localized Huckebein repressor, whereas miR-1 is activated by Dorsal and Twist. These results provide evidence that restricted activities of the 8-miR and miR-1 miRNAs are mediated by classical tissue-specific enhancers.

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