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Information on EC 1.14.11.68 - [histone H3]-trimethyl-L-lysine27 demethylase and Organism(s) Homo sapiens and UniProt Accession O15054
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1.14.11.68 [histone H3]-trimethyl-L-lysine27 demethylaseIUBMB Comments
Requires iron(II). This entry describes a group of enzymes that demethylate N-methylated L-lysine residues at position 27 of histone H3 (H3K27). The enzymes are dioxygenases and act by hydroxylating the methyl group, forming an unstable hemiaminal that leaves as formaldehyde. They can act on tri- and di-methylated forms, but have no activity with the mono-methylated form.
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Word Map
- 1.14.11.68
-
kabuki
- chromatin
-
facial
- demethylases
-
intellectual
- pik3ca
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arid1a
- crebbp
-
h3k4me3
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polycomb
- medicine
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muscle-invasive
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smarca4
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k-specific
- fat1
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gestalt
- gsk-j4
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
hide(Overall reactions are displayed. Show all >>)
Synonyms
kdm6a, lysine-specific demethylase 6b, lysine-specific demethylase 6a, jmjd-3.1, kdm6al, kdm6c, f18e9.5, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
JMJD3
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-
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KDM6A
KDM6C
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UTX
UTY
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KDM6A
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UTX
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SYSTEMATIC NAME
IUBMB Comments
[histone H3]-N6,N6,N6-trimethyl-L-lysine27,2-oxoglutarate:oxygen oxidoreductase
Requires iron(II). This entry describes a group of enzymes that demethylate N-methylated L-lysine residues at position 27 of histone H3 (H3K27). The enzymes are dioxygenases and act by hydroxylating the methyl group, forming an unstable hemiaminal that leaves as formaldehyde. They can act on tri- and di-methylated forms, but have no activity with the mono-methylated form.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
a [histine H3]-N6,N6,N6-trimethyllysine27 + 2 2-oxoglutarate + 2 O2
a [histine H3]-N6-methyllysine27 + 2 succinate + 2 formaldehyde + 2 CO2
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-
-
?
a [histone H3]-N6,N6,N6-trimethyl-L-lysine27 + 2 2-oxoglutarate + 2 O2
a [histone H3]-N6-methyl-L-lysine27 + 2 succinate + 2 formaldehyde + 2 CO2
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-
-
?
a [histone H3]-N6,N6,N6-trimethyl-L-lysine27 + 2-oxoglutarate + O2
a [histone H3]-N6,N6-dimethyl-L-lysine27 + succinate + formaldehyde + CO2
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-
-
?
a [histone H3]-N6,N6-dimethyl-L-lysine27 + 2-oxoglutarate + O2
a [histone H3]-N6-methyl-L-lysine27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 27 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2 2-oxoglutarate + 2 O2
[histone H3]-N6-methyllysine27 + 2 succinate + 2 formaldehyde + 2 CO2
[histone H3]-N6,N6,N6-trimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine27 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6-methyllysine27 + succinate + formaldehyde + CO2
[histone H3]-N6-methyllysine27 + 2-oxoglutarate + O2
[histone H3]-lysine27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2 2-oxoglutarate + 2 O2
[histone H3]-N6-methyllysine27 + 2 succinate + 2 formaldehyde + 2 CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2 2-oxoglutarate + 2 O2
[histone H3]-N6-methyllysine27 + 2 succinate + 2 formaldehyde + 2 CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine27 + succinate + formaldehyde + CO2
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?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine27 + succinate + formaldehyde + CO2
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?
[histone H3]-N6,N6-dimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6-methyllysine27 + succinate + formaldehyde + CO2
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-
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?
[histone H3]-N6,N6-dimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6-methyllysine27 + succinate + formaldehyde + CO2
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-
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?
[histone H3]-N6,N6-dimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6-methyllysine27 + succinate + formaldehyde + CO2
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?
additional information
?
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no substrates: methylated histone residues H3K4 and H3K9
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?
additional information
?
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monomethylated histone H3K27 is a poor substrate. No substrates: methylated histone residues H3K4, H3K9, H3K36, H3K79, and H4K20
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-
?
additional information
?
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UTX prefers H3K27me2 and H3K27me3 over H3K27me1 as substrates. No substrates: methylated histone residues H3K4, H3K9, and H3K36
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
[histone H3]-N6,N6,N6-trimethyl-L-lysine 27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 27 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 27 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2 2-oxoglutarate + 2 O2
[histone H3]-N6-methyllysine27 + 2 succinate + 2 formaldehyde + 2 CO2
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-
-
?
[histone H3]-N6,N6,N6-trimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine27 + succinate + formaldehyde + CO2
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-
-
?
[histone H3]-N6,N6-dimethyllysine27 + 2-oxoglutarate + O2
[histone H3]-N6-methyllysine27 + succinate + formaldehyde + CO2
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
GSK-J4
both the mRNA and protein levels of mPR3 are significantly reduced compared to controls
GSKJ4
inhibitor is active against native and temozolomide-resistant glioblastoma cells, albeit at at a lower effcacy than JIB 04, inhibitor of lysine demethylase KDM5A, EC 1.14.11.67. GSK J4 and JIB 04 strongly synergize and are a potent combination against temozolomide-resistant glioblastoma cells. GSK J4 does not synergize with temozolomide
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
neutrophil JMJD3 expression is increased in patients with sepsis
UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts
additional information
UTX is selectively excluded from the HOX loci in embryonic stem cells, in which HOX genes are largely silent
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
nuclear localization of Jmjd3 is required for effective demethylation of H3K27me3. The N-terminal region of the protein is responsible for its nuclear placement
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
physiological function
histone demethylase JMJD3 regulates the expression of neutrophil membrane proteinase 3 (mPR3, EC 3.4.21.76) in lipopolysaccharide-stimulated neutrophils, mostly during the early inflammatory response in sepsis. JMJD3 regulates the expression of mPR3 by changing the level of H3K27me3 in LPS-stimulated neutrophils
physiological function
JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development
physiological function
JMJD3 is associated with demethylase KIAA1718. JMJD3 and KIAA1718 directly bind to and regulate the expression of a plethora of common target genes in both a demethylase activity-dependent and -independent manner. JMJD3 and KIAA1718 collaborate to demethylate trimethylated H3K27 (H3K27me3) on a subset of their target genes. Reduction of either JMJD3 or KIAA1718 diminishes polymerase Pol II traveling along the gene bodies of the affected genes while having no effect on the promoter-proximal Pol II. JMJD3 and KIAA1718 also play a role in localizing elongation factors SPT6 and SPT16 to the target genes
physiological function
JMJD3 upregulation and NF-kappaB activation occur in the region of the wound edge during keratinocyte wound healing. JMJD3 interacts with NF-kappaB, resulting in increased expression of the inflammatory matrix metalloproteinase, and growth factor genes via demethylation of H3K27me3 at the gene promoters. Inactivation of JMJD3 or NF-kappaB results in aberrant keratinocyte wound healing
physiological function
transfection of JMJD3 into HeLa cells causes a specific reduction of trimethyl H3K27, but has no effect on di- and monomethyl H3K27, or histone lysine methylations on H3K4 and H3K9. The enzymatic activity requires the JmjC domain. JMJD3 directly catalyzes the demethylation
physiological function
JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development
physiological function
microRNA miR-142-3p binds directly to lysine demethylase 6A (KDM6A), which results in demethylation of H3K27me3 and in turn upregulated expression of the anti-apoptotic protein Bcl-2. miR-142-3p knockdown increases autophagy-related protein 16-1-mediated autophagy in in vitro induced human regulatory T cells
physiological function
RNAi inhibition of UTX leads to increased H3K27me3 levels at some HOX gene promoters
physiological function
UTX occupies the promoters of HOX gene clusters and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 and the monoubiquitination of histone H2A. UTX associates with mixed-lineage leukemia 2/3 complexes, and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4
physiological function
UTX specifically removes methyl marks on H3K27 in vitro. The demethylase activity of UTX requires a catalytically active JmjC domain. Overexpression of UTX leads to reduced di- and trimethylation on H3K27 in cells
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). KDM6B_HUMAN
1643
0
176632
Swiss-Prot
Mitochondrion (Reliability: 5)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structures of the catalytic fragment of UTX/KDM6A, in the free and H3 peptide-bound forms. The catalytic jumonji domain binds H3 residues 25-33, recognizing H3R26, H3A29, and H3P30 in a sequence-specific manner, in addition to H3K27me3 in the catalytic pocket. A zinc-binding domain, conserved within the KDM6 family, binds residues 17-21 of H3. The zinc-binding domain changes its conformation upon H3 binding, and thereby recognizes the H3L20 side chain via a hydrophobic patch on its surface, which is inaccessible in the H3-free form. Residues H3R17, H3L20, H3R26, H3A29, H3P30, and H3T32 are each important for demethylation
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E1148A
mutation in the catalytic JmjC-domain of UTX, abrogates enzymatic activity
H1146A
mutation in the catalytic JmjC-domain of UTX, abrogates enzymatic activity
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
GSK-J4 reduces both the mRNA and protein levels of mPR3 significantly compared to controls
JMJD3 is upregulated in prostate cancer, and its expression is higher in metastatic prostate cancer
lipopolysaccharide (LPS) induces JMJD3 expression in vitro. Neutrophil JMJD3 expression is increased in patients with sepsis compared to controls
presence of nickel chloride upregulates the expression of H3K27me3 demethylase Jmjd3 in kidney cancer cells, which is accompanied by the reduction in the protein level of H3K27me3
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
medicine
in renal cell carcinoma, UTX and JMJD3 transcripts are significantly increased compared to normal tissues. The level of trimethylated H3K27 is lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 is increased
medicine
JMJD3 is upregulated in prostate cancer, and its expression is higher in metastatic prostate cancer
medicine
JMJD3 upregulation and NF-kappaB activation occur in the region of the wound edge during keratinocyte wound healing. JMJD3 interacts with NF-kappaB, resulting in increased expression of the inflammatory matrix metalloproteinase, and growth factor genes via demethylation of H3K27me3 at the gene promoters. Inactivation of JMJD3 or NF-kappaB results in aberrant keratinocyte wound healing
medicine
presence of nickel chloride upregulates the expression of H3K27me3 demethylase Jmjd3 in kidney cancer cells, which is accompanied by the reduction in the protein level of H3K27me3
medicine
-
H3K27 methylation imposes ligand-dependent regulation of the estrogen receptor alpha-dependent apoptotic response via Bcl-2 in breast cancer cells. The activation of BCL2 transcription is dependent on the simultaneous inactivation of the H3K27 methyltransferase, EZH2, and the demethylation of H3K27 at a poised enhancer by the estrogen receptor alpha-dependent recruitment of JMJD3 in hormone-dependent breast cancer cells. This pathway is modified in cells resistant to anti-estrogen, which constitutively express BCL2
medicine
in renal cell carcinoma, UTX and JMJD3 transcripts are significantly increased compared to normal tissues. The level of trimethylated H3K27 is lower in cancer tissues compared to normal tissues, but expression of the H3K27 methyltransferase EZH2 is increased
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Na, J.; Lee, K.; Na, W.; Shin, J.; Lee, M.; Yune, T.; Lee, H.; Jung, H.; Kim, W.; Ju, B.
Histone H3K27 demethylase JMJD3 in cooperation with NF-kappaB regulates keratinocyte wound healing
J. Invest. Dermatol.
136
847-858
2016
Homo sapiens (O15054)
-
Shen, Y.; Guo, X.; Wang, Y.; Qiu, W.; Chang, Y.; Zhang, A.; Duan, X.
Expression and significance of histone H3K27 demethylases in renal cell carcinoma
BMC Cancer
12
470
2012
Homo sapiens (O15054), Homo sapiens (O15550)
Gao, J.; Gu, J.; Pan, X.; Gan, X.; Ju, Z.; Zhang, S.; Xia, Y.; Lu, L.; Wang, X.
Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells
Cell Death Dis.
10
332
2019
Homo sapiens (O15550), Homo sapiens
Xiang, Y.; Zhu, Z.; Han, G.; Lin, H.; Xu, L.; Chen, C.D.
JMJD3 is a histone H3K27 demethylase
Cell Res.
17
850-857
2007
Homo sapiens (O15054)
Svotelis, A.; Bianco, S.; Madore, J.; Huppe, G.; Nordell-Markovits, A.; Mes-Masson, A.M.; Gevry, N.
H3K27 demethylation by JMJD3 at a poised enhancer of anti-apoptotic gene BCL2 determines ERalpha ligand dependency
EMBO J.
30
3947-3961
2011
Homo sapiens
Kamikawa, Y.F.; Donohoe, M.E.
The localization of histone H3K27me3 demethylase Jmjd3 is dynamically regulated
Epigenetics
9
834-841
2014
Homo sapiens (O15054), Mus musculus (Q5NCY0)
Sengoku, T.; Yokoyama, S.
Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A
Genes Dev.
25
2266-2277
2011
Homo sapiens (O15550)
Chen, S.; Ma, J.; Wu, F.; Xiong, L.J.; Ma, H.; Xu, W.; Lv, R.; Li, X.; Villen, J.; Gygi, S.P.; Liu, X.S.; Shi, Y.
The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation
Genes Dev.
26
1364-1375
2012
Homo sapiens (O15054)
Chen, Y.; Liu, Z.; Pan, T.; Chen, E.; Mao, E.; Chen, Y.; Tan, R.; Wang, X.; Tian, R.; Liu, J.; Qu, H.
JMJD3 is involved in neutrophil membrane proteinase 3 overexpression during the hyperinflammatory response in early sepsis
Int. Immunopharmacol.
59
40-46
2018
Homo sapiens (O15054)
Lan, F.; Bayliss, P.E.; Rinn, J.L.; Whetstine, J.R.; Wang, J.K.; Chen, S.; Iwase, S.; Alpatov, R.; Issaeva, I.; Canaani, E.; Roberts, T.M.; Chang, H.Y.; Shi, Y.
A histone H3 lysine 27 demethylase regulates animal posterior development
Nature
449
689-694
2007
Danio rerio (A1L1S9), Homo sapiens (O15550)
Agger, K.; Cloos, P.A.; Christensen, J.; Pasini, D.; Rose, S.; Rappsilber, J.; Issaeva, I.; Canaani, E.; Salcini, A.E.; Helin, K.
UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development
Nature
449
731-734
2007
Caenorhabditis elegans (Q95QK3), Caenorhabditis elegans, Homo sapiens (O15054), Homo sapiens (O15550), Homo sapiens
Hong, S.; Cho, Y.W.; Yu, L.R.; Yu, H.; Veenstra, T.D.; Ge, K.
Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases
Proc. Natl. Acad. Sci. USA
104
18439-18444
2007
Homo sapiens (O15550)
Lee, M.G.; Villa, R.; Trojer, P.; Norman, J.; Yan, K.P.; Reinberg, D.; Di Croce, L.; Shiekhattar, R.
Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination
Science
318
447-450
2007
Homo sapiens (O15550)
Guo, X.; Zhang, Y.; Zhang, Q.; Fa, P.; Gui, Y.; Gao, G.; Cai, Z.
The regulatory role of nickel on H3K27 demethylase JMJD3 in kidney cancer cells
Toxicol. Ind. Health
32
1286-92
2016
Homo sapiens (O15054)
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