The lncRNA MIR31HG regulates p16 INK4A expression to modulate senescence

Marta Montes; Morten M. Nielsen; Giulia Maglieri; Anders Jacobsen; Jonas Højfeldt; Shuchi Agrawal-Singh; Klaus Hansen; Kristian Helin; Harmen J.G. Van De Werken; Jakob S. Pedersen; Anders H. Lund

doi:10.1038/ncomms7967

The lncRNA MIR31HG regulates p16 INK4A expression to modulate senescence

Marta Montes, Morten M. Nielsen, Giulia Maglieri, Anders Jacobsen, Jonas Højfeldt, Shuchi Agrawal-Singh, Klaus Hansen, Kristian Helin, Harmen J.G. Van De Werken, Jakob S. Pedersen, Anders H. Lund^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › Academic › peer-review

147 Citations (Scopus)

Abstract

Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16^INK4A -dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16^INK4A expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16^INK4A.

Original language	English
Article number	6967
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7967
Publication status	Published - 24 Apr 2015

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© 2015 Macmillan Publishers Limited. All rights reserved.

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title = "The lncRNA MIR31HG regulates p16 INK4A expression to modulate senescence",

abstract = "Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16INK4A -dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16INK4A expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16INK4A.",

author = "Marta Montes and Nielsen, {Morten M.} and Giulia Maglieri and Anders Jacobsen and Jonas H{\o}jfeldt and Shuchi Agrawal-Singh and Klaus Hansen and Kristian Helin and {Van De Werken}, {Harmen J.G.} and Pedersen, {Jakob S.} and Lund, {Anders H.}",

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AU - Montes, Marta

AU - Nielsen, Morten M.

AU - Maglieri, Giulia

AU - Jacobsen, Anders

AU - Højfeldt, Jonas

AU - Agrawal-Singh, Shuchi

AU - Hansen, Klaus

AU - Helin, Kristian

AU - Van De Werken, Harmen J.G.

AU - Pedersen, Jakob S.

AU - Lund, Anders H.

PY - 2015/4/24

Y1 - 2015/4/24

N2 - Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16INK4A -dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16INK4A expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16INK4A.

AB - Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16INK4A -dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16INK4A expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16INK4A.

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JO - Nature Communications

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The lncRNA MIR31HG regulates p16 INK4A expression to modulate senescence

Abstract

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