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histone H3 N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine9 + succinate + formaldehyde + CO2
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histone H3 N6-methyl-L-lysine9 + 2-oxoglutarate + O2
histone H3 L-lysine9 + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine9 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine9 + 2 succinate + 2 formaldehyde + 2 CO2
[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
additional information
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[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine9 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine9 + 2 succinate + 2 formaldehyde + 2 CO2
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[histone H3]-N6,N6-dimethyl-L-lysine9 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine9 + 2 succinate + 2 formaldehyde + 2 CO2
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Jmjd2c is recruited to the P2 promoter region of Mdm2 gene resulting in demethylation of histone H3 lysine 9, as typically found in actively transcribed genes
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[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
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[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
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additional information
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Kdm3a can specifically remove mono- or di-methyl residues from H3K9me1 or H3K9me2 to regulate gene transcription
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additional information
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no activity with histone H3 N6,N6,N6-trimethyl-L-lysine9
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additional information
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enzyme additionally mediates arginine demethylation of H4R3me2s and its intermediate, H4R3me1. Demethylation of H4R3me2s and H3K9me2s in promoter regions is correlated with active gene expression
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additional information
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the bifunctional enzyme catalyzes the demethylation of H3K4me2/me1 (EC 1.14.99.66) and H3K9me2/me1
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additional information
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the bifunctional enzyme catalyzes the demethylation of H3K9me2/me1 and H3K4me2/me1 (EC 1.14.99.66)
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histone H3 N6,N6-dimethyl-L-lysine9 + 2-oxoglutarate + O2
histone H3 N6-methyl-L-lysine9 + succinate + formaldehyde + CO2
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histone H3 N6-methyl-L-lysine9 + 2-oxoglutarate + O2
histone H3 L-lysine9 + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine9 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine9 + 2 succinate + 2 formaldehyde + 2 CO2
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Jmjd2c is recruited to the P2 promoter region of Mdm2 gene resulting in demethylation of histone H3 lysine 9, as typically found in actively transcribed genes
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?
[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
additional information
?
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Kdm3a can specifically remove mono- or di-methyl residues from H3K9me1 or H3K9me2 to regulate gene transcription
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 9 + succinate + formaldehyde + CO2
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[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
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[histone H3]-N6-methyl-L-lysine 9 + 2-oxoglutarate + O2
[histone H3]-L-lysine 9 + succinate + formaldehyde + CO2
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evolution
KDM3A is a histone demethylase in the JmjC domain-containing protein family
metabolism
expression of histone H3 Lys 9 demethylases Jmjd1a and Jmjd2c (EC 1.14.11.66) is positively correlated with the pluripotent state of ES and iPS cells. Jmjd1a and Jmjd2c regulate the global levels of H3K9Me2 and H3K9Me3, respectively
additional information
transient hyperglycemia induces recruitment of LSD1 to gene regulation sites/promoters. Transient hyperglycemia causes a sustained reduction in both H3K9m2 and H3K9m3 on the NFkappaB-p65 promoter
malfunction
knockout of Kdm3a increases H3K9me1 and H3K9me2 in the mammary epithelial cells. Knockout of Kdm3a results in retarded mammary gland ductal growth. Comparison of mammary gland ductal morphogenesis in wild-type and Kdm3a knockout virgin mice, overview. Kdm3a knockout shows no obvious effect on mammary gland tumor initiation but significantly reduces tumor growth
malfunction
depletion of LSD1 in an immortalized olfactory-placode-derived cell line (OP6) results in multigenic and multiallelic odorant receptor (OR) transcription per cell, while not seemingly disrupting the ability of these cells to activate new OR genes during clonal expansion. LSD1 depletion does not seem to alter OR representation in OP6 cell populations. Apparent systematic accumulation of H3K4me2 (and possibly H3K9me2) in LSD1-depleted cell populations
malfunction
Jmjd1a depletion leads to embryonic stem cell differentiation, which is accompanied by a reduction in the expression of embryonic stem cell-specific genes and an induction of lineage marker genes. The level of H3K9Me2, but not H3K9Me3, of total cell histone H3, is increased upon Jmjd1a knockdown. Knockdown of Jmjd1a does not appreciably affect Jmjd2c and vice versa
physiological function
histone modification alters chromatin architecture to regulate gene transcription. It removes di- and mono-methyl residues from di- or mono-methylated lysine 9 of histone H3 (H3K9me2/me1). Histone demethylase Kdm3a is required for normal epithelial proliferation ductal elongation and tumor growth in the mouse mammary gland. Kdm3a is not required for estrogen-induced ductal growth in the mammary gland. Kdm3a is required for normal proliferation and cyclin D1 expression in the mammary gland epithelial cells during the pubertal fast growing phase of mammary gland development. Kdm3a plays a direct role in upregulating cyclin D1 expression
physiological function
function of the mammalian olfactory system depends on specialized olfactory sensory neurons (OSNs) that each express only one allele of one odorant receptor (OR) gene (monogenic). The lysine-specific demethylase-1 (LSD1) has a role in silencing additional OR alleles in the immortalized olfactory-placode-derived cell line (OP6) cellular context. LSD1 protein removes activating H3K4 or silencing H3K9 methylation marks in a variety of developmental contexts
physiological function
Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. The loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. beta-Adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE
physiological function
Jmjd1a depletion leads to embryonic stem cell differentiation, which is accompanied by a reduction in the expression of embryonic stem cell-specific genes and an induction of lineage marker genes. Jmjd1a demethylates H3K9Me2 at the promoter regions of Tcl1, Tcfcp2l1, and Zfp57 and positively regulates the expression of these pluripotency-associated genes
physiological function
Jmjd1a is involved in the reversal of H3K9Me2 of bulk chromatin in embryonic stem cells. Jmjd1a demethylates H3K9Me2 at the promoter regions of Tcl1, Tcfcp2l1, and Zfp57 and positively regulates the expression of these pluripotency-associated genes, detailed overview. The embryonic stem cell transcription circuitry is connected to chromatin modulation through H3K9 demethylation in pluripotent cells
physiological function
Kdm3b knockout mice display restricted postnatal growth and female infertility. Kdm3b ablation decreases IGFBP-3 expressed in the kidney by 53% and significantly reduces IGFBP-3 in the blood, which causes an accelerated degradation of IGF-1 and a 36% decrease in circulating IGF-1 concentration. Knockout of Kdm3b in female mice causes irregular estrous cycles, decreases 45% of the ovulation capability and 47% of the fertilization rate, and reduces 44% of the uterine decidual response, which are accompanied with a more than 50% decrease in the circulating levels of the 17beta-estradiol, associated with significantly increased levels of H3K9me1/2/3 in the ovary and uterus
physiological function
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knockout of JMJD1B blocks demethylation of H4R3me2s and/or H3K9me2 at distinct clusters of genes and impairs the activation of genes important for hematopoietic stem/progenitor cell differentiation and development. JMJD1B-/- mice show defects in hematopoiesis
physiological function
LSD1 is a nuclear amine oxidase that utilizes oxygen as an electron acceptor to reduce methylated lysine to form lysine. It demethylates H3K4m1 and H3K4m2, as well as H3K9m1 and H3K9m2 as a removal of the active methylation mark. LSD1 is associated with co-repressor complexes and promotes suppression or activation of gene expression, e.g. LSD1 might be associated to cooperative recruitment to the NFkappaB p65 site for activation in hyperglycemia
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
Kdm3a promotes left ventricular hypertrophy and fibrosis in response to pressure-overload. KDM3A gene deletion protects mice against trans-aortic constriction-induced left ventricular hypertrophy. Cardiomyocyte KDM3A activates Timp1 transcription with profibrotic activity. A pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced left ventricular hypertrophy and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in KDM3A-knockout mice versus wild-type controls
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H1560A/D1562A/H1689A
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catalytically inactive mutant, carries mutations in the conserved cofactor (Fe2+) binding site
additional information
enzyme disruption mutant, and expression of a fusion protein consisting of the first 506 amino acids of the enzyme fused to a beta-galactosidase/neomycin cassette. The fusion protein lacks the catalytic domain. Presence of the active enzyme is essential for spermatogenesis. Mutant mice exhibit post-meiotic chromatin condensation defects. The enzyme binds directly to and controls the expression of transition nuclear protein 1 and protamine genes
additional information
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overexpression of wild-type Jmjd2c, but not of mutant H190A, increases the expression of Mdm2 oncogene dependent on its demethylase activity, which leads to the reduction of p53 tumor suppressor gene product in the cells
additional information
generation of Kdm3a knockout mice
additional information
construction of Jmjd1a knockout embryonic stem cells by RNAi assay, Jmjd1a depletion leads to embryonic stem cell differentiation, which is accompanied by a reduction in the expression of embryonic stem cell-specific genes and an induction of lineage marker genes. The same mutations that disrupt the in vitro Oct4/DNA interactions also abolish the enhancer activities. Knockdown of Jmjd1a does not appreciably affect Jmjd2c and vice versa
additional information
RNAi knockdown of LSD1 expression leads to undetectable levels in about 90% of olfactory-placode-derived cell line (OP-6) cells in culture, modeling. Apparent systematic accumulation of H3K4me2 (and possibly H3K9me2) in LSD1-depleted cell populations, overview
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Okada, Y.; Scott, G.; Ray, M.K.; Mishina, Y.; Zhang, Y.
Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis
Nature
450
119-123
2007
Mus musculus (Q6PCM1)
brenda
Ishimura, A.; Terashima, M.; Kimura, H.; Akagi, K.; Suzuki, Y.; Sugano, S.; Suzuki, T.
Jmjd2c histone demethylase enhances the expression of Mdm2 oncogene
Biochem. Biophys. Res. Commun.
389
366-371
2009
Mus musculus
brenda
Liu, Z.; Chen, X.; Zhou, S.; Liao, L.; Jiang, R.; Xu, J.
The histone H3K9 demethylase Kdm3b is required for somatic growth and female reproductive function
Int. J. Biol. Sci.
11
494-507
2015
Mus musculus (Q6ZPY7)
brenda
Vyas, R.N.; Meredith, D.; Lane, R.P.
Lysine-specific demethylase-1 (LSD1) depletion disrupts monogenic and monoallelic odorant receptor (OR) expression in an olfactory neuronal cell line
Mol. Cell. Neurosci.
82
1-11
2017
Mus musculus (Q6ZQ88)
brenda
Qin, L.; Xu, Y.; Yu, X.; Toneff, M.; Li, D.; Liao, L.; Martinez, J.; Li, Y.; Xu, J.
The histone demethylase Kdm3a is required for normal epithelial proliferation ductal elongation and tumor growth in the mouse mammary gland
Oncotarget
8
84761-84775
2017
Mus musculus (Q6PCM1)
brenda
Li, S.; Ali, S.; Duan, X.; Liu, S.; Du, J.; Liu, C.; Dai, H.; Zhou, M.; Zhou, L.; Yang, L.; Chu, P.; Li, L.; Bhatia, R.; Schones, D.; Wu, X.; Xu, H.; Hua, Y.; Guo, Z.; Yang, Y.; Zheng, L.; Shen, B.
JMJD1B demethylates H4R3me2s and H3K9me2 to facilitate gene expression for development of hematopoietic stem and progenitor cells
Cell Rep.
23
389-403
2018
Mus musculus
brenda
Brasacchio, D.; Okabe, J.; Tikellis, C.; Balcerczyk, A.; George, P.; Baker, E.K.; Calkin, A.C.; Brownlee, M.; Cooper, M.E.; El-Osta, A.
Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail
Diabetes
58
1229-1236
2009
Homo sapiens (O60341), Mus musculus (Q6ZQ88), Mus musculus C57BL/6 (Q6ZQ88)
brenda
Tachibana, M.; Nozaki, M.; Takeda, N.; Shinkai, Y.
Functional dynamics of H3K9 methylation during meiotic prophase progression
EMBO J.
26
3346-3359
2007
Mus musculus (Q6PCM1)
brenda
Loh, Y.; Zhang, W.; Chen, X.; George, J.; Ng, H.
Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells
Genes Dev.
21
2545-2557
2007
Mus musculus (Q6PCM1)
brenda
Loh, Y.H.; Zhang, W.; Chen, X.; George, J.; Ng, H.H.
Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells
Genes Dev.
21
254525-57
2007
Mus musculus (Q6PCM1)
brenda
Tateishi, K.; Okada, Y.; Kallin, E.; Zhang, Y.
Role of Jhdm2a in regulating metabolic gene expression and obesity resistance
Nature
458
757-761
2009
Mus musculus (Q6PCM1)
brenda
Zhou, J.; Wang, F.; Xu, C.; Zhou, Z.; Zhang, W.
The histone demethylase JMJD2A regulates the expression of BDNF and mediates neuropathic pain in mice
Exp. Cell Res.
361
155-162
2017
Homo sapiens (O75164), Mus musculus (Q8BW72), Mus musculus
brenda
Zhang, Q.J.; Tran, T.A.T.; Wang, M.; Ranek, M.J.; Kokkonen-Simon, K.M.; Gao, J.; Luo, X.; Tan, W.; Kyrychenko, V.; Liao, L.; Xu, J.; Hill, J.A.; Olson, E.N.; Kass, D.A.; Martinez, E.D.; Liu, Z.P.
Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis
Nat. Commun.
9
5230
2018
Mus musculus (Q6PCM1)
brenda