The TGFB2-AS1 lncRNA Regulates TGF-β Signaling by Modulating Corepressor Activity
Panagiotis Papoutsoglou,
Yutaro Tsubakihara,
Laia Caja,
Anita Morén,
Paris Pallis,
Adam Ameur,
Carl-Henrik Heldin,
Aristidis Moustakas
Affiliations
Panagiotis Papoutsoglou
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
Yutaro Tsubakihara
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
Laia Caja
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
Anita Morén
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
Paris Pallis
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
Adam Ameur
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Box 256, Uppsala University, 751 05 Uppsala, Sweden
Carl-Henrik Heldin
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
Aristidis Moustakas
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden; Corresponding author
Summary: 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. : Papoutsoglou et al. show that TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-β, interacts with the EED adaptor of the Polycomb repressor complex 2, and limits the response of target genes to TGF-β signaling. Keywords: corepressor, EED, EZH2, lncRNA, PRC2, signal transduction, Smad, SUZ12, TGF-β, transcription, tumor suppression
