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The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity

Abstract : 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.
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Submitted on : Monday, May 25, 2020 - 2:57:14 PM
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Panagiotis Papoutsoglou, Yutaro Tsubakihara, Laia Caja, Anita Moren, Paris Pallis, et al.. The TGFB2-AS1 lncRNA Regulates TGF-beta Signaling by Modulating Corepressor Activity. Cell Reports, Elsevier Inc, 2019, 28 (12), pp.3182-+. ⟨10.1016/j.celrep.2019.08.028⟩. ⟨hal-02363311⟩

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