JMJD3 is a histone H3K27 demethylase

Xiang, Yang; Zhu, Ziqi; Han, Gang; Lin, Hanqing; Xu, Longyong; Chen, Charlie Degui

doi:10.1038/cr.2007.83

Cited by 268 publications

(219 citation statements)

References 29 publications

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“…The GST-pull-down experiments demonstrated that GST-RB, but not GST alone, interacted with JMJD3 ( Figure 4c). The JmjC domain at the C-terminus has been identified as the only conserved catalytic domain of JMJD3, 36 as schematically illustrated in Figure 4d. Also, as mentioned above, the demethylase activity of JMJD3 was necessary for inducing cellular senescence (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

“…The substrate was incubated with the purified fusion protein of GST-JmjC domain of JMJD3 in demethylation buffer (20 mM TrisHCl pH 7.3, 150 mM NaCl, 50 μM (NH 4 )2Fe(SO 4 )2+6(H 2 O), 1 mM α-ketoglutarate and 2 mM ascorbic acid) for 4 h at 37°C. 36,41 Substrate was reacted in a total volume of 40 μl of reaction mixture. The reaction was stopped with SDS loading buffer, and western blotting analysis was performed.…”

Section: Discussionmentioning

confidence: 99%

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JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

et al. 2015

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Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), which can stabilize the state of senescence. The retinoblastoma (RB) protein has an important role in SAHF; cells that lack active RB pathway fail to form SAHF. It has been known that the posttranslational modifications of RB, for example, phosphorylation, regulate its function. To date, whether methylation of RB impacts on the SAHF formation is unknown. Here we report that JMJD3, a histone demethylase catalyzing the tri-methylation of H3K27 (H3K27me3), can demethylate the nonhistone protein RB at the lysine810 residue (K810), which is a target of the methyltransferase Set7/9. We detected a significant upregulation of JMJD3 during cellular senescence and SAHF formation in WI38 cells induced by H-RasV 12 , and we found that ectopic expression of JMJD3 promoted cellular senescence and SAHF formation in WI38 cells. Furthermore, during the process of SAHF assembly, JMJD3 was transported to the cytoplasm and interacted with RB through its demethylase domain JmjC. Significantly, our data demonstrated that the JMJD3-mediated demethylation of RB at K810 impeded the interaction of RB with the protein kinase CDK4 and resulted in reduced level of phosphorylation of RB at Serine807/811 (S807/811), implicating an important role of the interplay between the demethylation and phosphorylation of RB in SAHF assembly. This study highlights the role of JMJD3 as a novel inducer of SAHF formation through demethylating RB and provides new insights into the mechanisms of cellular senescence and SAHF assembly. Cellular senescence is an irreversible process of cell cycle arrest. The senescent cells remain metabolically active but are unable to express genes required for cell proliferation. 1,2 The known causes of cellular senescence include telomere shortening, oxidative stress, DNA damage and hyperoncogenic signaling. 3 H-RasV 12 has been used as a model to induce senescence in normal cells. [4][5][6] Senescent cells are typically characterized by a large flat morphology and the expression of a senescence-associated β-galactosidase activity (SA-β-gal), and nuclei of senescence cells may remodel to form the heterochromatin structures termed the senescenceassociated heterochromatin foci (SAHF). 7 SAHF are condensed regions of DNA that correlate with transcriptionally inactive sites. 8 These heterochromatin foci are hallmarked by H3K9me3 and the incorporation of heterochromatin protein HP1, macroH2A, PML (promyelocy leukemia protein) and HMGA1 (high mobility group AT-hook 1). 7,9-11 Recently, it has been shown that repressive markers, such as H3K9me3, H3K9me2 and H3K27me3, are rearranged into the nonoverlapping structural layers in SAHF. 12-14 Changes of heterochromatin organization generate a repressive chromatin environment that prevents transcription of genes that promote growth, thereby stabilize the state of senescence. 7,15 The retinoblastoma (RB) tumor suppressor is an important senesc...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

et al. 2015

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“…Methylation is added by histone methyltransferases and removed by demethylases. Up to now, more than 20 histone lysine demethylases have been identified that can remove methyl groups from histones in a sequence-and methylation state-specific manner [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. The histone lysine demethylases can be divided into two groups with different catalytic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans

Lin

Wang

et al. 2010

Cell Res

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H3K9me2 and H3K27me2 are important epigenetic marks associated with transcription repression, whileH3K4me3 is associated with transcription activation. It has been shown that active and repressive histone methylations distribute in a mutually exclusive manner, but the underlying mechanism was poorly understood. Here we identified ceKDM7A, a PHD (plant homeodomain)-and JmjC domain-containing protein, as a histone demethylase specific for H3K9me2 and H3K27me2. We further demonstrated that the PHD domain of ceKDM7A bound H3K4me3 and H3K4me3 co-localized with ceKDM7A at the genome-wide level. Disruption of the PHD domain binding to H3K4me3 reduced the demethylase activity in vivo, and loss of ceKDM7A reduced the expression of its associated target genes. These results indicate that ceKDM7A is recruited to the promoter to demethylate H3K9me2 and H3K27me2 and activate gene expression through the binding of the PHD domain to H3K4me3. Thus, our study identifies a dual-specificity histone demethylase and provides novel insights into the regulation of histone methylation.

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“…For example, lysine methylation at H3K9 is usually associated with regions of transcriptionally silenced chromatin. Recent studies indicate that histone methylation can be removed by two distinct classes of histone demethylases, namely, flavin adenine dinucleotide (FAD)-dependent [3] and JMJC-containing protein families [4][5][6][7]. The reversible process of histone methylation and demethylation has been implicated in multiple biological processes including heterochromatin formation, X-inactivation, genomic imprinting and silencing of homeotic genes.…”

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confidence: 99%

Structural insights into a novel histone demethylase PHF8

et al. 2010

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Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain (PHD) finger protein 8 (PHF8) are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate (α-KG) at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di-and mono-methylated histone H3 lysine 9 (H3K9me2/1), but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.

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JMJD3 is a histone H3K27 demethylase

Cited by 268 publications

References 29 publications

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

JMJD3 promotes SAHF formation in senescent WI38 cells by triggering an interplay between demethylation and phosphorylation of RB protein

Coordinated regulation of active and repressive histone methylations by a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans

Structural insights into a novel histone demethylase PHF8

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