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The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity
Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-8786-8763
Uppsala University, Science for Life Laboratory, SciLifeLab.
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 28, no 12, p. 3182-3198.ellArticle in journal (Refereed) Published
Abstract [en]

Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor beta (TGF-beta). Upon silencing individual lncRNAs, we identify several that regulate TGF-beta signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-beta through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-beta/Smad-mediated transcription and expression of hallmark TGF-beta-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-beta-induced cell growth arrest, and alters BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1, mainly via its 3' terminal region, binds to the EED adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me(3) modifications at TGF-beta-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-beta-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-beta/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-beta/BMP-mediated responses.

Place, publisher, year, edition, pages
CELL PRESS , 2019. Vol. 28, no 12, p. 3182-3198.ell
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Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-395306DOI: 10.1016/j.celrep.2019.08.028ISI: 000486389400014PubMedID: 31533040OAI: oai:DiVA.org:uu-395306DiVA, id: diva2:1362309
Funder
Swedish Cancer Society, CAN2015/438Swedish Research Council, K2013-66X-14936-10-5Swedish Research Council, 2015-02757EU, European Research Council, 787472Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-18Bibliographically approved

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Papoutsoglou, PanagiotisTsubakihara, YutaroCaja, LaiaMorén, AnitaAmeur, AdamHeldin, Carl-HenrikMoustakas, Aristidis
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