Abstract
The JmjC domain-containing protein JMJD3/KDM6B catalyses the demethylation of H3K27me3 and H3K27me2. JMJD3 appears to be highly regulated at the transcriptional level and is upregulated in response to diverse stimuli such as differentiation inducers and stress signals. Accordingly, JMJD3 has been linked to the regulation of different biological processes such as differentiation of embryonic stem cells, inflammatory responses in macrophages, and induction of cellular senescence via regulation of the INK4A-ARF locus. Here we show here that JMJD3 interacts with the tumour suppressor protein p53. We find that the interaction is dependent on the p53 tetramerization domain. Following DNA damage, JMJD3 is transcriptionally upregulated and by performing genome-wide mapping of JMJD3, we demonstrate that it binds genes involved in basic cellular processes, as well as genes regulating cell cycle, response to stress and apoptosis. Moreover, we find that JMJD3 binding sites show significant overlap with p53 bound promoters and enhancer elements. The binding of JMJD3 to p53 target sites is increased in response to DNA damage, and we demonstrate that the recruitment of JMJD3 to these sites is dependent on p53 expression. Therefore, we propose a model in which JMJD3 is recruited to p53 responsive elements via its interaction with p53 and speculate that JMJD3 could act as a fail-safe mechanism to remove low levels of H3K27me3 and H3K27me2 to allow for efficient acetylation of H3K27.
Highlights
The N-terminal tails of histone proteins are subject to various post-translational modifications including methylation of lysine residues
JMJD3 protein levels were increased in response to ionizing radiation (IR) (Fig. 2a), which is consistent with our previous results, in which we demonstrated upregulation of JMJD3 in response to UV-induced DNA damage [20]
Using available data on the distribution of H3K4me3 and H3K27me3 in BJ cells [34,35], we found that JMJD3 targeted promoters were strongly associated with the activating H3K4me3 mark and depleted for H3K27me3 (Fig. S3a and S3c) corresponding to the reported enzymatic activity of JMJD3 and in agreement with previously reported genome-wide binding data of JMJD3 obtained in LPS-induced macrophages [19]
Summary
The N-terminal tails of histone proteins are subject to various post-translational modifications including methylation of lysine residues. Histone modifications have been implicated in the regulation of genomic stability and cell fate decisions, as well as pathological processes such as cancer development. Di- and tri-methylation of histone 3 lysine 27 (H3K27me2/ me3) is catalysed by the Polycomb Repressive Complex 2 (PRC2), and is associated with transcriptional repression. The Polycomb group (PcG) proteins are essential for normal development in Drosophila and mammals, and are found as key regulators of genes involved in cellular differentiation and stem cell identity [1,2,3,4]. PcG proteins can repress the expression of certain tumour suppressor genes, including the INK4A-ARF locus [5,6,7,8] and overexpression of PcG proteins has been implicated in cancer development [9,10]
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