MiR-146a Wild-type 3' Sequence Identity is Dispensable for Proper Innate Immune Function in Vivo

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2019 Feb 20

PMID 30777858

Citations 5

Authors

Grant Bertolet

Natee Kongchan

Rebekah Miller

Ravi K Patel

Antrix Jain

Jong Min Choi

Alexander B Saltzman

Amber Christenson

Sung Yun Jung

Anna Malovannaya

Andrew Grimson

Joel R Neilson

Affiliations

Soon will be listed here.

Abstract

The prevailing model of microRNA function is that the "seed region" (nt 2-8) is sufficient to mediate target recognition and repression. However, numerous recent studies have challenged this model, either by demonstrating extensive 3' pairing between physically defined miRNA-mRNA pairs or by showing in that disrupted 3' pairing can result in impaired function in vivo. To test the importance of miRNA 3' pairing in a mammalian system in vivo, we engineered a mutant murine allele in which the 5' half of the mature microRNA retains its wild-type sequence, but the 3' half's sequence has been altered to robustly disrupt predicted pairing to this latter region. Mice homozygous or hemizygous for this mutant allele are phenotypically indistinguishable from wild-type controls and do not recapitulate any of the immunopathology previously described for -null mice. Our results indicate that 3' pairing is dispensable for the established myeloid function of this key mammalian microRNA.

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References

Moore M, Scheel T, Luna J, Park C, Fak J, Nishiuchi E . miRNA-target chimeras reveal miRNA 3'-end pairing as a major determinant of Argonaute target specificity. Nat Commun. 2015; 6:8864. PMC: 4674787. DOI: 10.1038/ncomms9864. View

Lim L, Lau N, Garrett-Engele P, Grimson A, Schelter J, Castle J . Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005; 433(7027):769-73. DOI: 10.1038/nature03315. View

Lee R, Ambros V . An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001; 294(5543):862-4. DOI: 10.1126/science.1065329. View

Loeb G, Khan A, Canner D, Hiatt J, Shendure J, Darnell R . Transcriptome-wide miR-155 binding map reveals widespread noncanonical microRNA targeting. Mol Cell. 2012; 48(5):760-70. PMC: 3562697. DOI: 10.1016/j.molcel.2012.10.002. View

Broughton J, Lovci M, Huang J, Yeo G, Pasquinelli A . Pairing beyond the Seed Supports MicroRNA Targeting Specificity. Mol Cell. 2016; 64(2):320-333. PMC: 5074850. DOI: 10.1016/j.molcel.2016.09.004. View

Neilson J, Winslow M, Hur E, Crabtree G . Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity. 2004; 20(3):255-66. DOI: 10.1016/s1074-7613(04)00052-4. View

Kloosterman W, Wienholds E, Ketting R, Plasterk R . Substrate requirements for let-7 function in the developing zebrafish embryo. Nucleic Acids Res. 2004; 32(21):6284-91. PMC: 535676. DOI: 10.1093/nar/gkh968. View

Bartel D . Metazoan MicroRNAs. Cell. 2018; 173(1):20-51. PMC: 6091663. DOI: 10.1016/j.cell.2018.03.006. View

Chi S, Hannon G, Darnell R . An alternative mode of microRNA target recognition. Nat Struct Mol Biol. 2012; 19(3):321-7. PMC: 3541676. DOI: 10.1038/nsmb.2230. View

10.

Grosswendt S, Filipchyk A, Manzano M, Klironomos F, Schilling M, Herzog M . Unambiguous identification of miRNA:target site interactions by different types of ligation reactions. Mol Cell. 2014; 54(6):1042-1054. PMC: 4181535. DOI: 10.1016/j.molcel.2014.03.049. View

11.

Mansfield J, Harfe B, Nissen R, Obenauer J, Srineel J, Chaudhuri A . MicroRNA-responsive 'sensor' transgenes uncover Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nat Genet. 2004; 36(10):1079-83. DOI: 10.1038/ng1421. View

12.

Saltzman A, Leng M, Bhatt B, Singh P, Chan D, Dobrolecki L . gpGrouper: A Peptide Grouping Algorithm for Gene-Centric Inference and Quantitation of Bottom-Up Proteomics Data. Mol Cell Proteomics. 2018; 17(11):2270-2283. PMC: 6210220. DOI: 10.1074/mcp.TIR118.000850. View

13.

Wissink E, Fogarty E, Grimson A . High-throughput discovery of post-transcriptional cis-regulatory elements. BMC Genomics. 2016; 17:177. PMC: 4778349. DOI: 10.1186/s12864-016-2479-7. View

14.

Jeong G, Lim Y, Kim N, Wee G, Kim Y . Knockout of miR-221 and miR-222 reveals common and specific targets for paralogous miRNAs. RNA Biol. 2016; 14(2):197-205. PMC: 5324760. DOI: 10.1080/15476286.2016.1269994. View

15.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

16.

Chi S, Zang J, Mele A, Darnell R . Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature. 2009; 460(7254):479-86. PMC: 2733940. DOI: 10.1038/nature08170. View

17.

Wong N, Wang X . miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2014; 43(Database issue):D146-52. PMC: 4383922. DOI: 10.1093/nar/gku1104. View

18.

Doench J, Petersen C, Sharp P . siRNAs can function as miRNAs. Genes Dev. 2003; 17(4):438-42. PMC: 195999. DOI: 10.1101/gad.1064703. View

19.

Brancati G, Grosshans H . An interplay of miRNA abundance and target site architecture determines miRNA activity and specificity. Nucleic Acids Res. 2018; 46(7):3259-3269. PMC: 5909448. DOI: 10.1093/nar/gky201. View

20.

Helwak A, Kudla G, Dudnakova T, Tollervey D . Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell. 2013; 153(3):654-65. PMC: 3650559. DOI: 10.1016/j.cell.2013.03.043. View