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

Cell Rep. 2019 Sep 17;28(12):3182-3198.e11. doi: 10.1016/j.celrep.2019.08.028.

Abstract

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.

MeSH terms

  • A549 Cells
  • Cell Cycle Checkpoints*
  • Humans
  • RNA, Antisense / genetics
  • RNA, Antisense / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Signal Transduction*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • RNA, Antisense
  • RNA, Long Noncoding
  • Transforming Growth Factor beta