Younger, ST and Corey, DR. Transcriptional regulation by miRNA mimics that target sequences downstream of gene termini. Mol Biosyst 7: 2383-2388
ABSTRACT Transcriptome studies have revealed that protein-coding loci within the human genome are overlapped at their 3'-termini by noncoding RNA (ncRNA) transcripts. Small duplex RNAs designed to be fully complementary to these 3' ncRNAs can modulate transcription of the upstream gene. Robust regulation by designed RNAs suggests that endogenous small RNAs might also recognize 3' ncRNAs and regulate gene expression. A genome-wide evaluation revealed that sequences immediately downstream of protein-coding genes are enriched with miRNA target sites. We experimentally tested miRNA mimics complementary to the well-characterized 3'-terminus of the human progesterone receptor (PR) gene and observed inhibition of PR transcription. These results suggest that recognition of ncRNA transcripts that overlap gene termini may be a natural function of endogenous small RNAs.
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- "Certain microRNAs mediate the induction of cell death, cell cycle arrest, autophagy and senescence and contribute to epithelial stem cell maturation    . On the one hand, microRNAs were recently shown to directly bind to gene promoter and gene terminus sequences, thereby modulating specific gene transcription  . On the other hand, transcriptional networks that are often deregulated in cancer cells may lead to altered transcription of specific microRNA genes . "
ABSTRACT: The tumor protein p63/microRNA functional network appears to play a decisive role in chemoresistance of human epithelial cancers. The cisplatin- and phosphorylated-ΔNp63α- dependent microRNAs, whose expression was varied in sensitive and resistant squamous cell carcinoma cells (SCC, which were derived from larynx and tongue tumors), were shown to modulate the expression of multiple members of cell cycle arrest, apoptosis and autophagy pathways. The specific microRNAs were further shown to modulate the resistant phenotype of SCC cells in vitro, thereby providing groundwork for novel chemotherapeutic venues for head and neck cancer.FEBS letters 07/2013; 587(16). DOI:10.1016/j.febslet.2013.06.020 · 3.17 Impact Factor
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- "By interacting with members of the Argonaute (Ago) subfamily of proteins (1), miRNAs mainly target homologous sites in 3′ untranslated regions (UTRs) to suppress translation (3) and/or degrade mRNA in a mechanism known as RNA interference (RNAi). Cases in which miRNAs target 5′-UTRs (4,5), coding regions (6), promoters (7,8), or sequences downstream of gene termini (9) to silence gene expression have also been reported, raising the possibility of multiple modes of action for miRNAs. Complexity of miRNA-mediated gene regulation is further expanded by observations that miRNAs can positively affect gene expression. "
ABSTRACT: It is largely recognized that microRNAs (miRNAs) function to silence gene expression by targeting 3'UTR regions. However, miRNAs have also been implicated to positively-regulate gene expression by targeting promoter elements, a phenomenon known as RNA activation (RNAa). In the present study, we show that expression of mouse Cyclin B1 (Ccnb1) is dependent on key factors involved in miRNA biogenesis and function (i.e. Dicer, Drosha, Ago1 and Ago2). In silico analysis identifies highly-complementary sites for 21 miRNAs in the Ccnb1 promoter. Experimental validation identified three miRNAs (miR-744, miR-1186 and miR-466d-3p) that induce Ccnb1 expression in mouse cell lines. Conversely, knockdown of endogenous miR-744 led to decreased Ccnb1 levels. Chromatin immunoprecipitation (ChIP) analysis revealed that Ago1 was selectively associated with the Ccnb1 promoter and miR-744 increased enrichment of RNA polymerase II (RNAP II) and trimethylation of histone 3 at lysine 4 (H3K4me3) at the Ccnb1 transcription start site. Functionally, short-term overexpression of miR-744 and miR-1186 resulted in enhanced cell proliferation, while prolonged expression caused chromosomal instability and in vivo tumor suppression. Such phenotypes were recapitulated by overexpression of Ccnb1. Our findings reveal an endogenous system by which miRNA functions to activate Ccnb1 expression in mouse cells and manipulate in vivo tumor development/growth.Nucleic Acids Research 11/2011; 40(4):1695-707. DOI:10.1093/nar/gkr934 · 9.11 Impact Factor
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ABSTRACT: Small RNAs are a commonly used tool for gene silencing and a promising platform for nucleic acid drug development. They are almost exclusively used to silence gene expression post-transcriptionally through degradation of mRNA. Small RNAs, however, can have a broader range of function by binding to Argonaute proteins and associating with complementary RNA targets in the nucleus, including long noncoding RNAs (lncRNAs) and pre-mRNA. Argonaute-RNA complexes can regulate nuclear events like transcription, genome maintenance, and splicing. Thousands of lncRNAs and alternatively spliced pre-mRNA isoforms exist in humans, and these RNAs may serve as natural targets for regulation and therapeutic intervention. This review describes nuclear mechanisms for Argonaute proteins and small RNAs, new pathways for sequence-specific targeting, and the potential for therapeutic development of small RNAs with nuclear targets.02/2012; 22(1):3-16. DOI:10.1089/nat.2011.0330