The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence

Karl Agger; Paul A.C. Cloos; Lise Rudkjær; Kristine Williams; Gitte Andersen; Jesper Christensen; Kristian Helin

doi:10.1101/gad.510809

The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence

Biotech Research and Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, DK-2200 Copenhagen, Denmark

Abstract

The tumor suppressor proteins p16^INK4A and p14^ARF, encoded by the INK4A–ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS–RAF signaling pathway. JMJD3 is recruited to the INK4A–ARF locus and contributes to the transcriptional activation of p16^INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16^Ink4a and p19^Arf expression and in their immortalization.

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Footnotes

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↵1 Corresponding author.

↵E-MAIL kristian.helin{at}bric.ku.dk; FAX 45-3532-5669.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.510809.
Supplemental material is available at http://www.genesdev.org.
- Received October 20, 2008.
- Accepted March 27, 2009.