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Information on EC 1.14.11.69 - [histone H3]-trimethyl-L-lysine36 demethylase and Organism(s) Mus musculus and UniProt Accession Q8BW72
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1.14.11.69 [histone H3]-trimethyl-L-lysine36 demethylaseIUBMB Comments
Requires iron(II). This entry describes a group of enzymes that demethylate N-methylated Lys36 residues in the tail of the histone protein H3 (H3K36). This lysine residue can exist in three methylation states (mono-, di- and trimethylated), but this group of enzymes only act on the the tri- and di-methylated forms. The enzymes are dioxygenases and act by hydroxylating the methyl group, forming an unstable hemiaminal that leaves as formaldehyde. Since trimethylation of H3K36 enhances transcription, this enzyme acts as a transcription repressor. The enzymes that possess this activity often also catalyse the activity of EC 1.14.11.66, [histone H3]-trimethyl-L-lysine9 demethylase. cf. EC 1.14.11.27, [histone H3]-dimethyl-L-lysine36 demethylase.
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Word Map
- 1.14.11.69
-
demethylation
- demethylases
- chromatin
-
jumonji
-
trimethylation
- fbxl10
-
polycomb
-
heterochromatic
- hp1a
- analysis
- medicine
The taxonomic range for the selected organisms is: Mus musculus
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
jmjc protein, jmjc demethylase, histone h3k36 demethylase, h3k36 histone demethylase, jmjd-2, rph1/kdm4, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
JHDM3A
-
-
-
-
JMJD2A
-
-
-
-
JMJD2B
KDM4A
-
-
-
-
KDM4B
Rph1
-
-
-
-
additional information
JMJD2B
-
-
-
-
KDM4B
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
[histone H3]-N6,N6,N6-trimethyl-L-lysine36,2-oxoglutarate:oxygen oxidoreductase
Requires iron(II). This entry describes a group of enzymes that demethylate N-methylated Lys36 residues in the tail of the histone protein H3 (H3K36). This lysine residue can exist in three methylation states (mono-, di- and trimethylated), but this group of enzymes only act on the the tri- and di-methylated forms. The enzymes are dioxygenases and act by hydroxylating the methyl group, forming an unstable hemiaminal that leaves as formaldehyde. Since trimethylation of H3K36 enhances transcription, this enzyme acts as a transcription repressor. The enzymes that possess this activity often also catalyse the activity of EC 1.14.11.66, [histone H3]-trimethyl-L-lysine9 demethylase. cf. EC 1.14.11.27, [histone H3]-dimethyl-L-lysine36 demethylase.
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
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyllysine36 + 2 2-oxoglutarate + 2 O2
[histone H3]-lysine36 + 2 succinate + 2 formaldehyde + 2 CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyllysine36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyllysine36 + 2-oxoglutarate + O2
[histone H3]-lysine36 + succinate + formaldehyde + CO2
-
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
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 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
additional information
additional information
Jmjd2a and Jmjd2c both localize to H3K4me3-positive regions. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
-
additional information
Jmjd2a and Jmjd2c both localize to H3K4me3-positive regions. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
-
additional information
Jmjd2a and Jmjd2c both localize to H3K4me3-positive regions. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
-
additional information
Jmjd2a and Jmjd2c both localize to H3K4me3-positive regions. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
-
additional information
Jmjd2a and Jmjd2c both localize to H3K4me3-positive regions. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
-
additional information
Jmjd2a and Jmjd2c both localize to H3K4me3-positive regions. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
the enzyme belongs to the Jmjd2 family of H3K9/H3K36 histone demethylases
malfunction
lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. While individual Jmjd2 family members are dispensable for embryonic stem cell maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired embryonic stem cell (ESC) self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions, phenotype, overview. Only specific genomic elements are affected upon loss of Jmjd2 function. Loss of Jmjd2a and Jmjd2c has a drastic effect on ESC proliferation
physiological function
evolution
the enzyme belongs to the Jmjd2 family of H3K9/H3K36 histone demethylases
malfunction
physiological function
physiological function
Jmjd2a and Jmjd2c both localize to H3K4me3-positive promoters, where they have widespread and redundant roles in preventing accumulation of H3K9me3 and H3K36me3. Jmjd2 catalytic activity is required for embryonic stem cell (ESC) maintenance. Jmjd2a and Jmjd2c are essential for early embryonic development. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes. Jmjd2a and Jmjd2c redundantly regulate histone methylation levels
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
depletion of KDM4A in prostate cancer cells inhibits their proliferation and survival in vivo and vitro. Deubiquitinase USP1 regulates KDM4A K48-linked deubiquitination and stability. c-Myc is a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving prostate cancer cell proliferation. Upregulation of KDM4A expression with high USP1 expression is observed in most prostate tumors and inhibition of USP1 promotes prostate cancer cells response to therapeutic agent enzalutamide
malfunction
lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. Only specific genomic elements are affected upon loss of Jmjd2 function
malfunction
lack of either Jmjd2a or Jmjd2b is compatible with embryonic stem cell self-renewal and embryonic development. While individual Jmjd2 family members are dispensable for embryonic stem cell maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired embryonic stem cell (ESC) self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions, phenotype, overview. Only specific genomic elements are affected upon loss of Jmjd2 function. Loss of Jmjd2a and Jmjd2c has a drastic effect on ESC proliferation
physiological function
in mouse embryonic fibroblasts engineered for the inducible expression of KDM4B, upon inducing Kdm4b, H3K9/36me3 levels significantly decrease compared to non-induced controls, and H3K9me1 levels significantly increase, while H3K9me2 and H3K27me3 remain unchanged. Reduced H3K9/36me3 levels are restored after somatic nuclear transfer
physiological function
Jmjd2a and Jmjd2c both localize to H3K4me3-positive promoters, where they have widespread and redundant roles in preventing accumulation of H3K9me3 and H3K36me3. Jmjd2 catalytic activity is required for embryonic stem cell (ESC) maintenance. Jmjd2a and Jmjd2c are essential for early embryonic development. Recruitment of the Jmjd2 H3K9/H3K36 demethylases to H3K4me3-marked nucleosomes. Jmjd2a and Jmjd2c redundantly regulate histone methylation levels
physiological function
histone H3.3 G34R substitution mutation, found in paediatric gliomas, causes widespread changes in H3K9me3 and H3K36me3 level by interfering with the KDM4 family of K9/K36 demethylases. Expression of a targeted single-copy of H3.3 G34R at endogenous levels induces chromatin alterations that are comparable to a KDM4 isoforms A/B/C triple-knockout. H3.3 G34R preferentially binds KDM4 while simultaneously inhibiting its enzymatic activity
physiological function
KDM4 activity is required for hematopoietic stem cell (HSC) maintenance in vivo. The combined knockout of Kdm4a, Kdm4b, and Kdm4c leads to reduction of myeloid and lymphoid cells. In conditional KDM4A/B/C triple-knockout mice, the knockout leads to accumulation of H3K9me3 on transcription start sites and the corresponding downregulation of expression of several genes in HSCs. Genes Taf1b and Nom1, are essential for the maintenance of hematopoietic 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). KDM4A_MOUSE
1064
0
120334
Swiss-Prot
other Location (Reliability: 2)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
generation of conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). While individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. Increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity. Phenotypes, overview
additional information
generation of conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). While individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. Increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity. Phenotypes, overview
additional information
generation of conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). While individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. Increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity. Phenotypes, overview
additional information
generation of conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). While individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. Increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity. Phenotypes, overview
additional information
generation of conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). While individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. Increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity. Phenotypes, overview
additional information
generation of conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). While individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions. Increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity. Phenotypes, overview
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene KDM4A/Jmjd2a, the loci encoding Jmjd2a and Jmjd2c are both located on chromosome 4 about 40 MB apart and are thus expected to co-segregate with a frequency related to the rate of meiotic recombination
gene KDM4C/Jmjd2c, the loci encoding Jmjd2a and Jmjd2c are both located on chromosome 4 about 40 MB apart and are thus expected to co-segregate with a frequency related to the rate of meiotic recombination
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
KDM4A expression is upregulated in phosphatase and tensin homolog knockout mouse prostate tissue
mRNA and protein levels of Jmjd2a are significantly increased in the neurons of mouse undergoing neuropathic pain
upon 4-hydroxytamoxifen treatment, Jmjd2a and Jmjd2b become undetectable by Western blot, while expression levels for other Jmjd2 family members are unaltered
Jmjd2c expression is unaffected by 4-hydroxytamoxifen treatment, while Jmjd2a and Jmjd2b are downregulated
upon 4-hydroxytamoxifen treatment, Jmjd2a and Jmjd2b become undetectable by Western blot, while expression levels for other Jmjd2 family members are unaltered
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
histone H3.3 G34R substitution mutation, found in paediatric gliomas, causes widespread changes in H3K9me3 and H3K36me3 level by interfering with the KDM4 family of K9/K36 demethylases. Expression of a targeted single-copy of H3.3 G34R at endogenous levels induces chromatin alterations that are comparable to a KDM4 A/B/C triple-knockout. H3.3 G34R preferentially binds KDM4 while simultaneously inhibiting its enzymatic activity
medicine
JMJD2A responds to neuropathic pain and participates in the maintenance of neuropathic pain. The mRNA and protein levels of Jmjd2a are significantly increased in the neurons of mouse undergoing neuropathic pain. 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
medicine
KDM4A expression is upregulated in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in prostate cancer cells inhibits their proliferation and survival in vivo and vitro. Upregulation of KDM4A expression with high USP1 expression is observed in most prostate tumors and inhibition of USP1 promotes prostate cancer cells response to therapeutic agent enzalutamide
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Pedersen, M.T.; Kooistra, S.M.; Radzisheuskaya, A.; Laugesen, A.; Johansen, J.V.; Hayward, D.G.; Nilsson, J.; Agger, K.; Helin, K.
Continual removal of H3K9 promoter methylation by Jmjd2 demethylases is vital for ESC self-renewal and early development
EMBO J.
35
1550-1564
2016
Mus musculus (Q8BW72), Mus musculus (Q8VCD7), Mus musculus (Q91VY5), Mus musculus C57BL/6 (Q8BW72), Mus musculus C57BL/6 (Q8VCD7), Mus musculus C57BL/6 (Q91VY5)
Wei, J.; Antony, J.; Meng, F.; MacLean, P.; Rhind, R.; Laible, G.; Oback, B.
KDM4B-mediated reduction of H3K9me3 and H3K36me3 levels improves somatic cell reprogramming into pluripotency
Sci. Rep.
7
7514
2017
Mus musculus (Q91VY5)
Agger, K.; Nishimura, K.; Miyagi, S.; Messling, J.E.; Rasmussen, K.D.; Helin, K.
The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance
Blood
134
1154-1158
2019
Mus musculus (Q91VY5)
Cui, S.Z.; Lei, Z.Y.; Guan, T.P.; Fan, L.L.; Li, Y.Q.; Geng, X.Y.; Fu, D.X.; Jiang, H.W.; Xu, S.H.
Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy
Cancer Sci.
111
1567-1581
2020
Mus musculus (Q8BW72)
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
Mus musculus (Q8BW72)
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