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The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-8786-8763
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2018 (English)Article in journal (Refereed) Submitted
Abstract [en]

LncRNAs regulate cell function through many physiological processes. We have identified lncRNAs whose expression is regulated by transforming growth factor β (TGFβ), by a transcriptomic screen. We focused on TGFB2-antisense RNA1 (TGFB2-AS1), which was induced by TGFβ through Smad and protein kinase pathways, and exhibited predominantly nuclear localization. Depleting TGFB2-AS1 enhanced TGFβ/Smad-mediated transcription and expression of the TGFβ-target genes FN1 and SERPINE1. Overexpression of TGFB2-AS1 reduced expression of these genes, attenuated TGFβ-induced cell growth arrest, and altered BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1 mainly via its 3’ terminal region, bound to EED, an adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me3 modifications at TGFβ-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity, partially rescued TGFB2-AS1 mediated gene repression. Our observations support the notion that TGFB2-AS1 is a TGFβ-induced lncRNA with inhibitory functions on TGFβ and BMP pathways output, constituting an auto-regulatory negative feedback mechanism that balances TGFβ- and BMP-mediated responses.

Place, publisher, year, edition, pages
2018.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-363700OAI: oai:DiVA.org:uu-363700DiVA, id: diva2:1257437
Available from: 2018-10-20 Created: 2018-10-20 Last updated: 2018-12-03
In thesis
1. Regulation of TGFβ signaling by long non-coding RNAs and ADP-ribosylation
Open this publication in new window or tab >>Regulation of TGFβ signaling by long non-coding RNAs and ADP-ribosylation
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor β (TGFβ) signaling pathways participate in embryonic development and tissue homeostasis and have a dual role in cancer. TGFβ acts as a tumor suppressor that promotes cell cycle arrest and apoptosis at initial stages of tumorigenesis. In contrast, TGFβ, induces epithelial to mesenchymal transition (EMT), a normal embryonic process which is employed by advanced cancers, in order to acquire mesenchymal traits and metastasize.

Bone morphogenetic protein (BMP) family members belong to the TGFβ superfamily and are involved in cell differentiation, development and bone formation.

Non-coding RNAs (ncRNAs) are not translated into proteins, are important regulators of gene expression and physiological processes and are often de-regulated in cancer. They control gene expression through physical association with chromatin, DNA, RNA molecules or proteins.

Poly(ADP-ribose) polymerases (PARPs) catalyze the poly (ADP)-ribosylation of proteins, whereas the enzyme poly(ADP-ribose) glycohydrolase (PARG) removes ADP-ribose units. Members of the PARP family function in the DNA damage response, regulation of transcription and cell death.

In this thesis, we investigated the importance of the TGFβ signaling pathway in regulating the expression of long non-coding RNAs (lncRNAs). We identified TGFβ-regulated lncRNAs and observed that a substantial number of them act in a feedback loop to modulate the magnitude of TGFβ signaling. Interestingly, the nuclear lncRNA TGFB2-antisense RNA 1 (TGFB2-AS1) is induced by TGFβ and negatively regulates expression of members of the TGFβ and BMP pathways, through interaction with EED, a protein of the polycomb repressor complex 2 (PRC2). Also, TGFβ signaling promoted the expression of mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG), which enhanced TGFβ signaling and affected TGFβ-mediated cell cycle arrest. The MIR100HG-derived miRNAs let-7a-2-3p, miR125b-5p and miR-125b-1-3p, were also induced by TGFβ. In contrast, the long intergenic non-protein coding RNA 707 (LINC00707), was reduced in response to TGFβ and affected the expression of a group of genes related to inflammatory responses and interferon-γ (IFN-γ) signaling.

We also report that TGFβ and BMP pathways are regulated by ADP-ribosylation of Smad proteins, the signaling mediators of these pathways. We observed that PARP1 and PARP2 attenuated, while PARG favored TGFβ signaling. Furthermore, PARP1 negatively regulated BMP signaling, by ADP-ribosylating Smad1 and Smad5, whereas PARG enhanced BMP signaling by de-ADP-ribosylating Smads.

Collectively, we provide evidence that lncRNAs and ADP-ribosylating enzymes modulate TGFβ and BMP signaling pathways and propose models for their molecular mechanisms and functional roles.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1513
Keywords
TGFβ, signal transduction, long non-coding RNAs, ADP-ribosylation, transcriptional regulation, chromatin remodeling
National Category
Cell and Molecular Biology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-364107 (URN)978-91-513-0497-7 (ISBN)
Public defence
2018-12-17, B42, Biomedical Center, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-11-22 Created: 2018-10-23 Last updated: 2018-11-30

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Papoutsoglou, PanagiotisTsubakihara, YutaroCaja, LaiaAmeur, AdamHeldin, Carl-HenrikMoustakas, Aristidis

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Ludwig Institute for Cancer ResearchScience for Life Laboratory, SciLifeLabDepartment of Medical Biochemistry and MicrobiologyThe Linnaeus Centre for BioinformaticsGenomicsDepartment of Immunology, Genetics and Pathology
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