The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene Silencing

Department of Experimental Oncology, European Institute of Oncology, Campus IFOM-IEO, Via Adamello 16, 20139 Milan, Italy.
Cell (Impact Factor: 32.24). 10/2007; 130(6):1083-94. DOI: 10.1016/j.cell.2007.08.019
Source: PubMed


Epigenetic chromatin marks restrict the ability of differentiated cells to change gene expression programs in response to environmental cues and to transdifferentiate. Polycomb group (PcG) proteins mediate gene silencing and repress transdifferentiation in a manner dependent on histone H3 lysine 27 trimethylation (H3K27me3). However, macrophages migrated into inflamed tissues can transdifferentiate, but it is unknown whether inflammation alters PcG-dependent silencing. Here we show that the JmjC-domain protein Jmjd3 is a H3K27me demethylase expressed in macrophages in response to bacterial products and inflammatory cytokines. Jmjd3 binds PcG target genes and regulates their H3K27me3 levels and transcriptional activity. The discovery of an inducible enzyme that erases a histone mark controlling differentiation and cell identity provides a link between inflammation and reprogramming of the epigenome, which could be the basis for macrophage plasticity and might explain the differentiation abnormalities in chronic inflammation.

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Available from: Samuele Notarbartolo,
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    • "How JMJD3 becomes localized at specific genomic regions is not well known, but emerging evidence indicates that transcription factors such as SMAD3 and HES1 are involved (Dai et al., 2010; Estará s et al., 2012). JMJD3 has also been found in trithorax group (trxG) chromatin remodeling complexes (De Santa et al., 2007), and trxG family member Mll1 is required for SVZ neurogenesis (Lim et al., 2009). In SVZ cells, we found both MLL1 and JMJD3 proteins localized at I12b, and JMJD3 enrichment at this enhancer was lost in Mll1-deleted cells. "
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    ABSTRACT: The epigenetic mechanisms that enable lifelong neurogenesis from neural stem cells (NSCs) in the adult mammalian brain are poorly understood. Here, we show that JMJD3, a histone H3 lysine 27 (H3K27) demethylase, acts as a critical activator of neurogenesis from adult subventricular zone (SVZ) NSCs. JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation. JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements. JMJD3 localizes at neural enhancers genome-wide in embryonic brain, and in SVZ NSCs, JMJD3 regulates the I12b enhancer of Dlx2. In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails. These findings support a model in which JMJD3 and the poised state of key transcriptional regulatory elements comprise an epigenetic mechanism that enables the activation of neurogenic gene expression in adult NSCs throughout life.
    Cell Reports 08/2014; 8(5). DOI:10.1016/j.celrep.2014.07.060 · 8.36 Impact Factor
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    • "However, knowledge of NF-κB gene targets in neurons is limited, with only a few genes, such as the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) and pro-survival members of the Bcl2 family, having been established as NF-κB targets that protect against apoptosis (Mattson et al., 1997; Tamatani et al., 1999; Zong et al., 1999). Interestingly, the Kdm6b promoter contains binding sites for the NF-κB family of transcription factors, and in macrophages , the induction of Kdm6b by inflammatory stimuli occurs in an NF-κB-dependent manner (De Santa et al., 2007). NF-κB-dependent transcription is strongly activated in cultured hippocampal neurons following synaptic glutamate receptor activation (Meffert et al., 2003). "
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    ABSTRACT: Enzymes that regulate histone lysine methylation play important roles in neuronal differentiation, but little is known about their contributions to activity-regulated gene transcription in differentiated neurons. We characterized activity-regulated expression of lysine demethylases and lysine methyltransferases in the hippocampus of adult male mice following pilocarpine-induced seizure. Pilocarpine drove a 20-fold increase in mRNA encoding the histone H3 lysine27-specific demethylase Kdm6b selectively in granule neurons of the dentate gyrus, and this induction was recapitulated in cultured hippocampal neurons by bicuculline and 4-aminopyridine (Bic+4AP) stimulation of synaptic activity. Because activity-regulated gene expression is highly correlated with neuronal survival, we tested the requirement for Kdm6b expression in Bic+4AP induced preconditioning of neuronal survival. Prior exposure to Bic+4AP promoted neuronal survival in control neurons upon growth factor withdrawal, however this effect was ablated when we knocked down Kdm6b expression. Loss of Kdm6b did not disrupt activity-induced expression of most genes, including that of a gene set previously established to promote neuronal survival in this assay. However using bioinformatic analysis of RNA sequencing data, we discovered that Kdm6b knockdown neurons showed impaired inducibility of a discrete set of genes annotated for their function in inflammation. These data reveal a novel function for Kdm6b in activity-regulated neuronal survival, and they suggest that activity- and Kdm6b-dependent regulation of inflammatory gene pathways may serve as an adaptive pro-survival response to increased neuronal activity.
    Molecular and Cellular Neuroscience 06/2014; 61. DOI:10.1016/j.mcn.2014.06.008 · 3.84 Impact Factor
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    • "Unlike UTX, 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. For instance, JMJD3 is dynamically expressed during differentiation of embryonic stem cells [17] and keratinocytes [18], and is highly upregulated in inflammatory stimulated bone marrow-derived macrophages [12], [19]. Furthermore, JMJD3 possesses tumour suppressor characteristics and is upregulated in response to oncogenic stress, where it contributes to activation of the INK4A-ARF locus [20], [21]. "
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    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.
    PLoS ONE 05/2014; 9(5):e96545. DOI:10.1371/journal.pone.0096545 · 3.23 Impact Factor
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