Dicer Dependent TRNA Derived Small RNAs Promote Nascent RNA Silencing

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2022 Jan 20

PMID 35048990

Authors

Arianna Di Fazio

Margarita Schlackow

Sheng Kai Pong

Adele Alagia

Monika Gullerova

Affiliations

Soon will be listed here.

Abstract

In mammalian cells, small non-coding RNAs (sncRNAs) negatively regulate gene expression in a pathway known as RNA interference (RNAi). RNAi can be categorized into post-transcriptional gene silencing (PTGS), which involves the cleavage of target messenger RNA (mRNA) or inhibition of translation in the cytoplasm, and transcriptional gene silencing (TGS), which is mediated by the establishment of repressive epigenetic marks at target loci. Transfer RNAs (tRNAs), which are essential for translation, can be processed into small ncRNAs, termed tRNA-derived small RNAs (tsRNAs). The biogenesis of tsRNAs and their role in gene expression regulation has not yet been fully understood. Here, we show that Dicer dependent tsRNAs promote gene silencing through a mechanism distinct from PTGS and TGS. tsRNAs can lead to downregulation of target genes by targeting introns via nascent RNA silencing (NRS) in nuclei. Furthermore, we show that Ago2 slicer activity is required for this mechanism. Synthetic tsRNAs can significantly reduce expression of a target gene at both RNA and protein levels. Target genes regulated by NRS are associated with various diseases, which further underpins its biological significance. Finally, we show that NRS is evolutionarily conserved and has the potential to be explored as a novel synthetic sRNA based therapeutic.

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References

Kumar P, Anaya J, Mudunuri S, Dutta A . Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets. BMC Biol. 2014; 12:78. PMC: 4203973. DOI: 10.1186/s12915-014-0078-0. View

Gonzalez S, Pisano D, Serrano M . Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs. Cell Cycle. 2008; 7(16):2601-8. DOI: 10.4161/cc.7.16.6541. View

Hasler D, Lehmann G, Murakawa Y, Klironomos F, Jakob L, Grasser F . The Lupus Autoantigen La Prevents Mis-channeling of tRNA Fragments into the Human MicroRNA Pathway. Mol Cell. 2016; 63(1):110-24. DOI: 10.1016/j.molcel.2016.05.026. View

Kim Y, Kim B, Kim V . Re-evaluation of the roles of DROSHA, Export in 5, and DICER in microRNA biogenesis. Proc Natl Acad Sci U S A. 2016; 113(13):E1881-9. PMC: 4822641. DOI: 10.1073/pnas.1602532113. View

Kim H, Fuchs G, Wang S, Wei W, Zhang Y, Park H . A transfer-RNA-derived small RNA regulates ribosome biogenesis. Nature. 2017; 552(7683):57-62. PMC: 6066594. DOI: 10.1038/nature25005. View

Maute R, Schneider C, Sumazin P, Holmes A, Califano A, Basso K . tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma. Proc Natl Acad Sci U S A. 2013; 110(4):1404-9. PMC: 3557069. DOI: 10.1073/pnas.1206761110. View

Zerbino D, Achuthan P, Akanni W, Amode M, Barrell D, Bhai J . Ensembl 2018. Nucleic Acids Res. 2017; 46(D1):D754-D761. PMC: 5753206. DOI: 10.1093/nar/gkx1098. View

OCarroll D, Mecklenbrauker I, Das P, Santana A, Koenig U, Enright A . A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 2007; 21(16):1999-2004. PMC: 1948855. DOI: 10.1101/gad.1565607. View

Enright A, John B, Gaul U, Tuschl T, Sander C, Marks D . MicroRNA targets in Drosophila. Genome Biol. 2004; 5(1):R1. PMC: 395733. DOI: 10.1186/gb-2003-5-1-r1. View

10.

Gagnon K, Li L, Chu Y, Janowski B, Corey D . RNAi factors are present and active in human cell nuclei. Cell Rep. 2014; 6(1):211-21. PMC: 3916906. DOI: 10.1016/j.celrep.2013.12.013. View

11.

Durinck S, Spellman P, Birney E, Huber W . Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. 2009; 4(8):1184-91. PMC: 3159387. DOI: 10.1038/nprot.2009.97. View

12.

Weinberg M, Villeneuve L, Ehsani A, Amarzguioui M, Aagaard L, Chen Z . The antisense strand of small interfering RNAs directs histone methylation and transcriptional gene silencing in human cells. RNA. 2005; 12(2):256-62. PMC: 1370905. DOI: 10.1261/rna.2235106. View

13.

Castel S, Martienssen R . RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013; 14(2):100-12. PMC: 4205957. DOI: 10.1038/nrg3355. View

14.

Drexler H, Choquet K, Churchman L . Splicing Kinetics and Coordination Revealed by Direct Nascent RNA Sequencing through Nanopores. Mol Cell. 2019; 77(5):985-998.e8. PMC: 7060811. DOI: 10.1016/j.molcel.2019.11.017. View

15.

Sarshad A, Juan A, Correa Muler A, Anastasakis D, Wang X, Genzor P . Argonaute-miRNA Complexes Silence Target mRNAs in the Nucleus of Mammalian Stem Cells. Mol Cell. 2018; 71(6):1040-1050.e8. PMC: 6690358. DOI: 10.1016/j.molcel.2018.07.020. View

16.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

17.

Hafner M, Lianoglou S, Tuschl T, Betel D . Genome-wide identification of miRNA targets by PAR-CLIP. Methods. 2012; 58(2):94-105. PMC: 3508682. DOI: 10.1016/j.ymeth.2012.08.006. View

18.

Su Z, Wilson B, Kumar P, Dutta A . Noncanonical Roles of tRNAs: tRNA Fragments and Beyond. Annu Rev Genet. 2020; 54:47-69. PMC: 7686126. DOI: 10.1146/annurev-genet-022620-101840. View

19.

Martinez G, Choudury S, Slotkin R . tRNA-derived small RNAs target transposable element transcripts. Nucleic Acids Res. 2017; 45(9):5142-5152. PMC: 5605234. DOI: 10.1093/nar/gkx103. View

20.

Wang Q, Lee I, Ren J, Ajay S, Lee Y, Bao X . Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection. Mol Ther. 2012; 21(2):368-79. PMC: 3594034. DOI: 10.1038/mt.2012.237. View