The TGFB2-AS1 lncRNA Regulates TGF-? 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 ? (TGF-?). Upon silencing individual lncRNAs, we identify several that regulate TGF-? signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-? through Smad and protein kinase pathways and resides in the nucleus. Depleting TGFB2-AS1 enhances TGF-?/Smad-mediated transcription and expression of hallmark TGF-?-target genes. Increased dose of TGFB2-AS1 reduces expression of these genes, attenuates TGF-?-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-?-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity partially rescues TGFB2-AS1-mediated gene repression. Thus, the TGF-?-induced TGFB2-AS1 lncRNA exerts inhibitory functions on TGF-?/BMP signaling output, supporting auto-regulatory negative feedback that balances TGF-?/BMP-mediated responses.

SUBMITTER: Papoutsoglou P 

PROVIDER: S-EPMC6859500 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature