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Natural antisense transcripts in diseases: From modes of action to targeted therapies

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Antisense transcription is a widespread phenomenon in mammalian genomes, leading to production of RNAs molecules referred to as natural antisense transcripts (NATs). NATs apply diverse transcriptional and post‐transcriptional regulatory mechanisms to carry out a wide variety of biological roles that are important for the normal functioning of living cells, but their dysfunctions can be associated with human diseases. In this review, we attempt to provide a molecular basis for the involvement of NATs in the etiology of human disorders such as cancers and neurodegenerative and cardiovascular diseases. We also discuss the pros and cons of oligonucleotide‐based therapies targeted against NATs, and we comment on state‐of‐the‐art progress in this promising area of clinical research. WIREs RNA 2018, 9:e1461. doi: 10.1002/wrna.1461 This article is categorized under: RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
Functions of NATs. (a) Chromatin remodeling by the PRC1 or PRC2 complexes recruited by the NAT. Me, H3K27me3 histone modification. (b) Regulation of the alternative splicing by the RNA:RNA interaction between pre‐mRNA and NAT within the 3′ end of the pre‐mRNA’s retained intron. (c) miRNA sponge formed by the increased amount of trans‐NATs possessing miRNA target sites. (d) miRNA masking by the RNA:RNA interaction between RNA and NAT within the miRNA target sequence
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Regulation of RNA levels using antisense oligonucleotides (ASO). (a) RNA level downregulation by the ASO gapmer. The RNA:gapmer duplex is recognized by the RNase H, which leads to transcript cleavage and degradation. (b) RNA level downregulation by small interfering RNA (siRNA). The siRNA is loaded into an RNA‐induced silencing complex with argonaute‐2 protein (AGO2), which leads to target transcript cleavage and degradation within the RNAi pathway. (c) Modulation of repressive epigenetic changes by the chromatin modifiers recognizing the ASO:RNA duplex. TSS, transcription start site; Ac, H3K27ac histone modification; Me, H3K27me3 histone modification
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RNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Disease

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