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TGFB2-AS1 lncRNA 通过调节核心抑制物活性来调控 TGF-β 信号通路。

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

机构信息

Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Ludwig Cancer Research Box 582, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden.

Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Box 256, Uppsala University, 751 05 Uppsala, Sweden.

出版信息

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

DOI:10.1016/j.celrep.2019.08.028
PMID:31533040
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6859500/
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 H3K27me 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.

摘要

涉及长链非编码 RNA (lncRNAs)的分子过程调节细胞功能。通过应用转录组学，我们确定了 lncRNAs 的表达受转化生长因子 β (TGF-β)调控。在沉默单个 lncRNAs 后，我们发现了一些调节 TGF-β信号通路的 lncRNAs。在这些 lncRNAs 中，TGFB2-antisense RNA1 (TGFB2-AS1) 通过 Smad 和蛋白激酶途径被 TGF-β诱导，并位于细胞核内。TGFB2-AS1 的消耗增强了 TGF-β/Smad 介导的转录和标志性 TGF-β 靶基因的表达。TGFB2-AS1 剂量增加会降低这些基因的表达，减弱 TGF-β诱导的细胞生长停滞，并改变 BMP 和 Wnt 通路基因谱。在机制上，TGFB2-AS1 主要通过其 3'端区域与多梳抑制复合物 2 (PRC2)的 EED 衔接子结合，促进 TGF-β 靶基因启动子上抑制性组蛋白 H3K27me 的修饰。沉默 EED 或抑制 PRC2 甲基化活性可部分挽救 TGFB2-AS1 介导的基因抑制。因此，TGF-β 诱导的 TGFB2-AS1 lncRNA 对 TGF-β/BMP 信号通路的输出发挥抑制作用，支持 TGF-β/BMP 介导的反应的自动负反馈调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/6b6cc5850696/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/171e3b2bbbd6/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/8053830fd3f0/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/06974f4d59c6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/5bf74ceea330/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/3d87eeb436fb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/23659366a296/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/d3ea42a9e1ca/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/6b6cc5850696/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/171e3b2bbbd6/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/8053830fd3f0/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/06974f4d59c6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/5bf74ceea330/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/3d87eeb436fb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/23659366a296/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/d3ea42a9e1ca/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27c5/6859500/6b6cc5850696/gr7.jpg

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