The H3K27me3 demethylase JMJD3 contributes to the activation of theINK4A–ARFlocus in response to oncogene- and stress-induced senescence

Abstract

The tumor suppressor proteins p16INK4A and p14ARF, 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 p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.

Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus

“…1A). [14,15]. We generated IMR90 qRT-PCR and immunofluorescence analyses were performed as described previously [36].…”

“…In response to Raf signal, induction of JMJD3 was followed by downregulation of EZH2 [14]. Knockdown of JMJD3 increased the expression of EZH2 but decreased the expression of INK4a, suggesting that JMJD3 mainly mediated Raf signaling to demethylate H3K27me3 of INK4a locus and also to decrease EZH2 expression [14]. Here, we investigated whether hypoxia indeed changes the histone methylation of the endogenous JMJD3 target, the INK4a gene, leading to changes in gene expression.…”

Epigenetic regulation of aging stem cells

“…Similarly, in the developing nervous system of mice, JMJD3 promotes differentiation upon induction of retinoic acid signaling, and its suppression is required for the maintenance of an uncommitted stem cell state (Jepsen et al, 2007). The role for JMJD3 in adult NSCs has not yet been determined, but altered JMJD3 activity in aging NSC populations may promote loss of a stem cell state by inappropriate initiation of differentiation programs or by de-repression of the p16 Ink4a /p19 Arf locus, as has been reported in fibroblasts (Agger et al, 2009;Barradas et al, 2009). Alternatively, failure of aged stem cells to induce Jmjd3 may render NSCs less responsive to differentiation signals and thereby contribute to decreased neurogenic potential of stem/progenitors during aging.…”

Pirin Inhibits Cellular Senescence in Melanocytic Cells

“…Human diploid fibroblasts (TIG3-hTERT) expressing a conditional form of constitutively activated BRAF fused to the ligand-binding domain of the estrogen receptor (ER) rapidly undergo oncogene-induced senescence on treatment with 4-hydroxytamoxifen (OHT). 28,29 PIR protein and mRNA levels were measured in TIG3-BRAF-ER cells at different time points of treatment with 800 nmol/L OHT. PIR expression was significantly repressed both at the mRNA and at the protein level after BRAF activation ( Figure 6A), and remained at low levels after 120 hours, suggesting that a significant reduction of PIR expression is associated with the establishment of oncogene-induced senescence in different cell types.…”