Small RNA-Guided Transcriptional Gene Activation (RNAa) in Mammalian Cells
Small RNA partnering with Argonaute (Ago) proteins plays important roles in diverse biological processes mainly by suppressing the expression of cognate target sequences. Mounting evidence reveals that the small RNA-Ago pathway can also positively regulat
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Small RNA-Guided Transcriptional Gene Activation (RNAa) in Mammalian Cells Long-Cheng Li
Abstract Small RNA partnering with Argonaute (Ago) proteins plays important roles in diverse biological processes mainly by suppressing the expression of cognate target sequences. Mounting evidence reveals that the small RNA-Ago pathway can also positively regulate gene expression, a phenomenon termed as RNA activation (RNAa), which is evolutionarily conserved from Caenorhabditis elegans to human. In this chapter, I provide a general overview of mammalian RNAa phenomena and their basic characteristics and discuss recent advances toward understanding the nature of the molecular machinery responsible for RNAa and the development of RNAa-based research tools and therapeutics. Keywords RNA activation • RNAa • Small activating RNA • saRNA • Transcription • Argonaute
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Introduction
Small RNA molecules of 20–26 nucleotides (nt) generated within the cells through multiple steps of processing can serve as a versatile and sequence-specific regulatory signal to affect the expression of longer nucleic acid sequences. Such regulation by small RNAs is largely achieved by partnering with Argonautes (Agos) proteins [32]. Agos belong to a highly evolutionarily conserved family of proteins, and once programmed by small RNAs, can function as a homology search engine which uses the sequence information of the small RNA as a querying keyword [21]. Besides matching small RNAs with cognate sequences, Agos assume additional tasks such as participating in biogenesis of small RNAs, executing catalytic activity on cognate sequences, serving as a platform for recruiting other proteins. The pathways formed by various types of small RNAs and Agos have mainly been associated with a function of suppressing or eliminating cognate nucleic acid sequences including RNA and DNA [41], and are mainly utilized by organisms
L.-C. Li (*) Laboratory of Molecular Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 L.-C. Li (ed.), RNA Activation, Advances in Experimental Medicine and Biology 983, DOI 10.1007/978-981-10-4310-9_1
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as a defense mechanism against the invasion of foreign sequences and harmful effects of mobile genetic elements. However, in mammalian cells such defense mechanisms have become obsolete during evolution and the pathway has been repurposed as a device for tuning the output of endogenous genes.
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A Historical View of RNAa
Back in 2006, in an attempt to address whether aberrant promoter hypermethylation occurring in cancer cells could be triggered by small RNAs, we designed short double-stranded RNAs (dsRNAs) to target the promoter of E-cadherin, a gene frequently silenced by promoter hypermethylation in human cancer cells. Unexpectedly, we found that dsRNAs could in fact induce the expression of E-cadherin. After reproducing this phenomenon with two additional genes, we were prompted to examine it in detail
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