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evolution
human JMJD2 (KDM4) H3K9 and H3K36 demethylases can be divided into members that act on both H3K9 and H3K36 and H3K9 alone, structural and phylogenetic analysis, overview. KDM4A/B/C act on both H3K9 and, less efficiently, on H3K36-methylated substrates, substrate selectivity of the human KDM4 histone demethylase subfamily, overview
evolution
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JMJD5/KDM8 is a member of the JmjC family
evolution
two families of lysine demethylases (KDM) are identified. The KDM4 family consists of four members: KDM4A, KDM4B, KDM4C and KDM4D
malfunction
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depletion of Kdm2b/Jhdm1b in hematopoietic progenitors significantly impairs Hoxa9/Meis1-induced leukemic transformation. In leukemic stem cells, knockdown of Kdm2b/Jhdm1b impairs their self-renewing capability in vitro and in vivo
malfunction
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Jhdm1a knockdown mice are still able to maintain normal glycemia, but display higher glucose production upon injection of the gluconeogenic substrate pyruvate
malfunction
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Jmjd5-/- embryos show severe growth retardation, resulting in embryonic lethality at the mid-gestation stage, Cdkn1a expression is upregulated in Jmjd5neo/neo MEFs and Jmjd5-/- embryos, which is responsible for the growth defects. phenotypes, overview. Jmjd5neo/neo hypomorphic mouse embryonic fibroblasts proliferate more slowly than wild-type
malfunction
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silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level in vivo
malfunction
changes in RENT component recruitment at NTS regions due to loss of H3 methylases or demethylases
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities. Depletion or overexpression of KDM4B does not leads to an increase in the frequency of abnormal mitotic cells and has no detectable effect on mitotic chromosome segregation
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities. Depletion or overexpression of KDM4C, but not KDM4B, leads to over 3fold increase in the frequency of abnormal mitotic cells showing either misaligned chromosomes at metaphase, anaphase-telophase lagging chromosomes or anaphase-telophase bridges. Overexpression of a KDM4C demethylase dead mutant has no detectable effect on mitotic chromosome segregation
malfunction
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Ndy1 knockdown by siRNA enhances sensitivity to oxidative stress, downregulation of Ndy1 activates the phosphorylation of AMPK, JNK, and p38MAPK and the cleavage of caspase-3 both before and after treatment with H2O2, Ndy1 overexpression protects cells against oxidative stress, overexpression of Ndy1 inhibits the phosphorylation of AMPK, JNK, and p38MAPK and the cleavage of caspase-3 both before and after treatment with H2O2. Knocking down Ndy1 sensitizes the cells to H2O2-induced oxidative stress. Genes Nqo1 and Prdx4 are direct Ndy1 targets. First, Ndy1 but not its DELTACXXC mutant binds specific regions in the promoters of both genes. Second, whereas Ndy1 upregulates their expression, the DELTACXXC mutant does not, suggesting that binding to the promoter region is necessary for their induction
malfunction
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Jhdm1a knockdown mice are still able to maintain normal glycemia, but display higher glucose production upon injection of the gluconeogenic substrate pyruvate
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metabolism
dKDM2 couples histone H2A ubiquitylation to histone H3 demethylation during Polycomb group gene silencing as a mode of histone crosstalk, the enzyme acts as part of the dRING-associated factor, dRAF, a Polycomb group silencing complex harboring also the histone H2A ubiquitin ligase dRING, Posterior sex combs and the F-box protein, overview. dRAF and PCR1 are separtate Polycomb group complexes, dKDM2 and PRC1 control overlapping transcriptomes, mechanisms, overview
metabolism
different roles of histone H3 methylases in regulating Net1/Sir2 recruitment to rDNA regions and the resultant rDNA silencing. In particular, both H3K4 and H3K79 methylation by Set1 and Dot1 positively regulate rDNA silencing, whereas H3K36 methylation by Set2 has the opposite effect
metabolism
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Ndy1 epigenetically regulates several redox genes and the regulation of these genes by Ndy1 is responsible for the modulation of H2O2 levels and for the resistance of Ndy1-expressing cells to oxidative stress. Genes Nqo1 and Prdx4 are direct Ndy1 targets
physiological function
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histone methyl-L-lysine marks display dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites
physiological function
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histone methyl-lysine marks display dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites
physiological function
in vivo, the enzyme cooperates with Polycomb but antagonizes gene activation by particular trxG methyltransferases, gene dkdm2 is an enhancer of Polycomb but a suppressor of histone methyltransferases trx and ash1
physiological function
the H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b), Jhdm1b targets the p15Ink4b locus and regulates its expression in an enzymatic activity-dependent manner, overview
physiological function
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JHDM1A plays an central role in gene silencing, cell cycle, cell growth and cancer development through histone H3K36 demethylation modification
physiological function
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demethylation of H3K36 reduces DSB repair. Expression of JHDM1a decreases the association of early NHEJ repair components with an induced DSB and decreased DSB repair
physiological function
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histone demethylase Jhdm1a regulates hepatic gluconeogenesis, regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Jhdm1a is a key negative regulator of gluconeogenic gene expression. Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPalpha, by its USF1-dependent association with the C/EBPa promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPa lpha locus
physiological function
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Jhdm1a has a physiological role in hepatic gluconeogenesis in vivo, and this role is mediated by its histone demethylation activity
physiological function
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Jmjd5 is involved in the maintenance of H3K36me2 at the Cdkn1a locus
physiological function
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Kdm2b/Jhdm1b functions as an oncogene and plays a critical role in leukemia development and maintenance, KDM2b/JHDM1b is required for initiation and maintenance of acute myeloid leukemia. Functions of Kdm2b/Jhdm1b are mediated by its silencing of p15Ink4b expression through active demethylation of histone H3-N6,N6-dimethyl-L-lysine. Kdm2b/Jhdm1b directly regulates p15Ink4b expression in leukemic cells
physiological function
changes in histone H3 lysine methylation levels distinctly regulate rDNA silencing by recruiting different silencing proteins to rDNA, thereby contributing to rDNA silencing and nucleolar organization in yeast. Jhd1 positively affects transcription
physiological function
the KDM4 isozymes are involved in histone methylation, a reversible and dynamically regulated process. Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate lysine residues on histone H3, i.e. H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. Isozyme KDM4A is not associated with chromatin during mitosis, in contrast to isozyme KDM4C
physiological function
the KDM4 isozymes are involved in histone methylation, a reversible and dynamically regulated process. Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate lysine residues on histone H3, i.e. H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. Isozyme KDM4B is not associated with chromatin during mitosis, in contrast to isozyme KDM4C
physiological function
the KDM4 isozymes are involved in histone methylation, a reversible and dynamically regulated process. Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate lysine residues on histone H3, i.e. H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. Isozyme KDM4D is not associated with chromatin during mitosis, in contrast to isozyme KDM4C
physiological function
the KDM4 isozymes are involved in histone methylation, a reversible and dynamically regulated process. Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate lysine residues on histone H3, i.e. H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. Unlike KDM4A-B, isozyme KDM4C is associated with chromatin during mitosis. This association is accompanied by a decrease in the mitotic levels of H3K9me3. The C-terminal region, containing the Tudor domains of KDM4C, is essential for its association with mitotic chromatin, especially residue R919 on the proximal Tudor domain of KDM4C is critical for its association with chromatin during mitosis. The demethylase activity and the mitotic localization of KDM4C influence the integrity of mitotic chromosome segregation
physiological function
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the JmjC domain histone demethylase Ndy1 regulates redox homeostasis and protects cells from oxidative stress. Ndy1 promotes the expression of genes encoding the antioxidant enzymes aminoadipic semialdehyde synthase (Aass), NAD(P)H quinone oxidoreductase-1 (Nqo1), peroxiredoxin-4 (Prdx4), and serine peptidase inhibitor b1b (Serpinb1b) and represses the expression of interleukin-19. At least two of these genes (Nqo1 and Prdx4) are regulated directly by Ndy1, which binds to specific sites within their promoters and demethylates promoter-associated histone H3 dimethylated at K36 and histone H3 trimethylated at K4. Simultaneous knockdown of Aass, Nqo1, Prdx4, and Serpinb1b in Ndy1-expressing cells to levels equivalent to those detected in control cells is sufficient to suppress the Ndy1 redox phenotype. The enzyme protects cells against oxidative stress by inhibiting reactive oxygen species-dependent signaling, overview. Ndy1 inhibits the oxidation of deoxyguanosine and DNA damage, and the accumulation of H2O2 in both H2O2-treated and untreated cells. Ndy1 enhances the antioxidant activity of cells. The gene Serpinb1b, upregulated by Ndy1, and gene IL-19, which is downregulated by Ndy1, play indirect roles in redox homeostasis, overview. Endogenous Ndy1 is a physiological redox regulator of the cellular response to oxidative stress. Ndy1 functions as an activator of transcription are in agreement with recently published data showing that Ndy1 promotes the transcriptional activation of the Hoxd1 gene. Ndy1 can also function as a repressor. Genes Nqo1 and Prdx4 are direct Ndy1 targets. First, Ndy1 but not its DELTACXXC mutant binds specific regions in the promoters of both genes. Second, whereas Ndy1 upregulates their expression, the DELTACXXC mutant does not, suggesting that binding to the promoter region is necessary for their induction
physiological function
JMJD5 has divalent cation-dependent protease activities that preferentially cleave the tails of histones 2, 3, or 4 containing methylated arginines. After the initial specific cleavage, JMJD5 acting as aminopeptidase, progressively digests the C-terminal products. JMJD5-deficient fibroblasts exhibit dramatically increased levels of methylated arginines and histones
physiological function
JMJD5 has divalent cation-dependent protease activities that preferentially cleave the tails of histones 2, 3, or 4 containing methylated arginines. After the initial specific cleavage, JMJD5 acting as aminopeptidase, progressively digests the C-terminal products. JMJD5-deficient fibroblasts exhibit dramatically increased levels of methylated arginines and histones. Depletion of JMJD7 in breast cancer cells greatly decreases cell proliferation
physiological function
catalyzes the demethylation of di- and trimethylated Lys9 (reactions of EC 1.14.11.65 and 1.14.11.66) and Lys36 in histone H3 (reactions of EC 1.14.11.27 and 1.14.11.69). Jmjd2a responds to 5-hydroxytryptamine and promotes the expression of the brain-derived neurotrophic factor (Bdnf), a protein critically involved in neuropathic pain. JMJD2A binds to the promoter of Bdnf and demethylates H3K9me3 and H3K36me3 at the Bdnf promoter to promote the expression of Bdnf
physiological function
catalyzes the demethylation of di- and trimethylated Lys9 (reactions of EC 1.14.11.65 and 1.14.11.66) and Lys36 in histone H3 (reactions of EC 1.14.11.27 and 1.14.11.69). Jmjd2a responds to 5-hydroxytryptamine and promotes the expression of the brain-derived neurotrophic factor (Bdnf), a protein critically involved in neuropathic pain. JMJD2A binds to the promoter of Bdnf and demethylates H3K9me3 and H3K36me3 at the Bdnf promoter to promote the expression of Bdnf. JMJD2A promotes the expression of Bdnf during neuropathic pain and neuron-specific knockout of Jmjd2a blocks the hypersensitivity of mice undergoing chronic neuropathic pain
physiological function
histone H3 lysine 36 demethylase activity of the CpG islands (CGI) binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters
physiological function
JmjC domain histone H3K36me2/me1 demethylase KDM2B is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impairs the survival of patient-derived primary glioblastoma cells through the induction of DNA damage and apoptosis and sensitizes them to chemotherapy. KDM2B loss decreases the cancer stem-like cells pool, which is potentiated by coadministration of chemotherapy
physiological function
KDM2B demethylates serum response factor residue K165 to negatively regulate muscle differentiation. KDM2B inhibits skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and histone methyltransferase SET7 regulate the balance of SRF K165 methylation. SRF K165 methylation is required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes
physiological function
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Jhdm1a has a physiological role in hepatic gluconeogenesis in vivo, and this role is mediated by its histone demethylation activity
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additional information
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ectopic expression of Kdm2b/Jhdm1b is sufficient to transform hematopoietic progenitors
additional information
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expression of the wild-type Jhdm1a, but not the H212A point mutant, decreased the expression of PEPCK and G6Pase in diabetic ob/ob mice
additional information
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nuclear protein Jmjd5 or Kdm8 is a histone lysine demethylase that contains a JmjC domain in the C-terminal region
additional information
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substrate selectivity is determined by multiple interactions within the catalytic domain but outside the active site, structural basis of sequence celectivity between KDM4 members, overview
additional information
substrate selectivity is determined by multiple interactions within the catalytic domain but outside the active site, structural basis of sequence celectivity between KDM4 members, overview
additional information
substrate selectivity is determined by multiple interactions within the catalytic domain but outside the active site, structural basis of sequence celectivity between KDM4 members, overview
additional information
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expression of the wild-type Jhdm1a, but not the H212A point mutant, decreased the expression of PEPCK and G6Pase in diabetic ob/ob mice
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