Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor β (TGF-β). Upon silencing individual lncRNAs, we identify several that regulate TGF-β signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-β through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-β/Smad-mediated transcription and expression of hallmark TGF-β-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-β-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 H3K27me3 modifications at TGF-β-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-β-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-β/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-β/BMP-mediated responses.
Keywords: EED; EZH2; PRC2; SUZ12; Smad; TGF-β; corepressor; lncRNA; signal transduction; transcription; tumor suppression.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.