Fendrr Synergizes with Wnt Signalling to Regulate Fibrosis Related Genes During Lung Development Via Its RNA:dsDNA Triplex Element

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2023 May 19

PMID 37207329

Authors

Tamer Ali

Sandra Rogala

Nina M Krause

Jasleen Kaur Bains

Maria-Theodora Melissari

Sandra Wahrisch

Harald Schwalbe

Bernhard G Herrmann

Phillip Grote

Affiliations

Soon will be listed here.

Abstract

Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via an RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and found that this FendrrBox is partially required for Fendrr function in vivo. We found that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in lung fibroblasts. We biophysically confirmed the formation of an RNA:dsDNA triplex with target promoters in vitro. We found that Fendrr with the Wnt signalling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signalling in lung fibrosis.

Citing Articles

Systematic study of hybrid triplex topology and stability suggests a general triplex-mediated regulatory mechanism.

Genna V, Portella G, Sala A, Terrazas M, Serrano-Chacon I, Gonzalez J Nucleic Acids Res. 2025; 53(5).

PMID: 40071936 PMC: 11897885. DOI: 10.1093/nar/gkaf170.

Oxidative stress controls lncRNA-mediated sow granulosa cell functions in a FoxO1-dependent manner.

Sheng W, Wang M, Li Y, Sun Z, Du X, Li Q J Anim Sci Biotechnol. 2024; 15(1):171.

PMID: 39681884 PMC: 11648296. DOI: 10.1186/s40104-024-01120-6.

A Mutation Losing an RBP-Binding Site in the LncRNA NORSF Transcript Influences Granulosa Cell Apoptosis and Sow Fertility.

Wang M, Sheng W, Zhang J, Cao Q, Du X, Li Q Adv Sci (Weinh). 2024; 11(40):e2404747.

PMID: 39120076 PMC: 11516108. DOI: 10.1002/advs.202404747.

Functional roles of conserved lncRNAs and circRNAs in eukaryotes.

Li J, Wang X Noncoding RNA Res. 2024; 9(4):1271-1279.

PMID: 39036601 PMC: 11260338. DOI: 10.1016/j.ncrna.2024.06.014.

Transcription regulation by long non-coding RNAs: mechanisms and disease relevance.

Ferrer J, Dimitrova N Nat Rev Mol Cell Biol. 2024; 25(5):396-415.

PMID: 38242953 PMC: 11045326. DOI: 10.1038/s41580-023-00694-9.

References

Hosseinzadeh A, Javad-Moosavi S, Reiter R, Hemati K, Ghaznavi H, Mehrzadi S . Idiopathic pulmonary fibrosis (IPF) signaling pathways and protective roles of melatonin. Life Sci. 2018; 201:17-29. DOI: 10.1016/j.lfs.2018.03.032. View

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

Huang C, Liang Y, Zeng X, Yang X, Xu D, Gou X . Long Noncoding RNA FENDRR Exhibits Antifibrotic Activity in Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2019; 62(4):440-453. PMC: 7110975. DOI: 10.1165/rcmb.2018-0293OC. View

Cao H, Wang C, Chen X, Hou J, Xiang Z, Shen Y . Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis. Sci Rep. 2018; 8(1):13644. PMC: 6134002. DOI: 10.1038/s41598-018-28968-9. View

Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H . g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019; 47(W1):W191-W198. PMC: 6602461. DOI: 10.1093/nar/gkz369. View

Li Y, Syed J, Sugiyama H . RNA-DNA Triplex Formation by Long Noncoding RNAs. Cell Chem Biol. 2016; 23(11):1325-1333. DOI: 10.1016/j.chembiol.2016.09.011. View

Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B . MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures. Nat Commun. 2015; 6:7743. PMC: 4525211. DOI: 10.1038/ncomms8743. View

Concordet J, Haeussler M . CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res. 2018; 46(W1):W242-W245. PMC: 6030908. DOI: 10.1093/nar/gky354. View

Herriges M, Swarr D, Morley M, Rathi K, Peng T, Stewart K . Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development. Genes Dev. 2014; 28(12):1363-79. PMC: 4066405. DOI: 10.1101/gad.238782.114. View

10.

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

11.

Manzini G, Xodo L, Gasparotto D, Quadrifoglio F, van der Marel G, VAN Boom J . Triple helix formation by oligopurine-oligopyrimidine DNA fragments. Electrophoretic and thermodynamic behavior. J Mol Biol. 1990; 213(4):833-43. DOI: 10.1016/S0022-2836(05)80267-0. View

12.

Hon C, Ramilowski J, Harshbarger J, Bertin N, Rackham O, Gough J . An atlas of human long non-coding RNAs with accurate 5' ends. Nature. 2017; 543(7644):199-204. PMC: 6857182. DOI: 10.1038/nature21374. View

13.

Polack F, Thomas S, Kitchin N, Absalon J, Gurtman A, Lockhart S . Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020; 383(27):2603-2615. PMC: 7745181. DOI: 10.1056/NEJMoa2034577. View

14.

Morse C, Tabib T, Sembrat J, Buschur K, Trejo Bittar H, Valenzi E . Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur Respir J. 2019; 54(2). PMC: 8025672. DOI: 10.1183/13993003.02441-2018. View

15.

Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R . Software for computing and annotating genomic ranges. PLoS Comput Biol. 2013; 9(8):e1003118. PMC: 3738458. DOI: 10.1371/journal.pcbi.1003118. View

16.

Grote P, Wittler L, Hendrix D, Koch F, Wahrisch S, Beisaw A . The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013; 24(2):206-14. PMC: 4149175. DOI: 10.1016/j.devcel.2012.12.012. View

17.

Konermann S, Brigham M, Trevino A, Joung J, Abudayyeh O, Barcena C . Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature. 2014; 517(7536):583-8. PMC: 4420636. DOI: 10.1038/nature14136. View

18.

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

19.

Xiao J, Hao Q, Wang K, Paul J, Wang Y . Emerging Role of MicroRNAs and Long Noncoding RNAs in Healthy and Diseased Lung. Adv Exp Med Biol. 2017; 967:343-359. DOI: 10.1007/978-3-319-63245-2_22. View

20.

Szafranski P, Dharmadhikari A, Brosens E, Gurha P, Kolodziejska K, Zhishuo O . Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder. Genome Res. 2012; 23(1):23-33. PMC: 3530681. DOI: 10.1101/gr.141887.112. View