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Information on EC 1.14.11.27 - [histone H3]-dimethyl-L-lysine36 demethylase and Organism(s) Mus musculus and UniProt Accession Q6P1G2
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1.14.11.27 [histone H3]-dimethyl-L-lysine36 demethylaseIUBMB Comments
Requires iron(II). Of the seven potential methylation sites in histones H3 (K4, K9, K27, K36, K79) and H4 (K20, R3) from HeLa cells, the enzyme is specific for Lys36. Lysine residues exist in three methylation states (mono-, di- and trimethylated). The enzyme preferentially demethylates the dimethyl form of Lys36 (K36me2), which is its natural substrate, to form the monomethylated and unmethylated forms of Lys36. It can also demethylate monomethylated (but not the trimethylated) Lys36. cf. EC 1.14.11.69, [histone H3]-trimethyl-L-lysine36 demethylase.
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Word Map
- 1.14.11.27
- demethylases
- chromatin
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demethylation
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h3k9me3
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trimethylation
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jumonji
- tumorigenesis
- methyltransferases
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lysine-specific
- heterochromatin
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tri-methylated
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tudor
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chromatin-modifying
- jmjd1a
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jmjc-domain-containing
- setdb1
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
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Synonyms
jmjd2a, kdm4b, kdm2b, kdm4a, kdm2a, kdm4c, lysine demethylase, jmjd5, kdm4d, gasc1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
SYSTEMATIC NAME
IUBMB Comments
[histone H3]-N6,N6-dimethyl-L-lysine36,2-oxoglutarate:oxygen oxidoreductase
Requires iron(II). Of the seven potential methylation sites in histones H3 (K4, K9, K27, K36, K79) and H4 (K20, R3) from HeLa cells, the enzyme is specific for Lys36. Lysine residues exist in three methylation states (mono-, di- and trimethylated). The enzyme preferentially demethylates the dimethyl form of Lys36 (K36me2), which is its natural substrate, to form the monomethylated and unmethylated forms of Lys36. It can also demethylate monomethylated (but not the trimethylated) Lys36. cf. EC 1.14.11.69, [histone H3]-trimethyl-L-lysine36 demethylase.
CAS REGISTRY NUMBER
COMMENTARY
55071-98-2
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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-dimethyl-L-lysine36 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine36 + 2 succinate + 2 formaldehyde + 2 CO2
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
protein C/EBPalpha-N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2
protein C/EBPalpha-N6-methyl-L-lysine + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
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?
[histone H3]-N6-methyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-L-lysine 36 + succinate + formaldehyde + CO2
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[histone H3]-N6,N6-dimethyl-L-lysine36 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine36 + 2 succinate + 2 formaldehyde + 2 CO2
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?
[histone H3]-N6,N6-dimethyl-L-lysine36 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine36 + 2 succinate + 2 formaldehyde + 2 CO2
the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15Ink4b as loss of p15Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells
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histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
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?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
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Jhdm1a is a histone demethylase that specifically demethylates dimethylated H3K36
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?
additional information
?
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substrate specificity of Jhdm1b in vivo using HEK293 cells overexpressing the enzyme, overview
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?
additional information
?
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substrate specificity of Jhdm1b in vivo using HEK293 cells overexpressing the enzyme, overview
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?
additional information
?
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Jhdm1b, like its paralogue, JHDM1A, can specifically demethylate H3K36me2 and H3K36me1 histone substrates, but they are not active on methylated Lys4
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?
additional information
?
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Jhdm1b, like its paralogue, JHDM1A, can specifically demethylate H3K36me2 and H3K36me1 histone substrates, but they are not active on methylated Lys4
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?
additional information
?
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the enzyme is active on H3 trimethylated at K4 and dimethylated at K36, it might preferentially demethylate H3 trimethylated at K4 (EC 1.14.11.67)
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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-dimethyl-L-lysine36 + 2 2-oxoglutarate + 2 O2
[histone H3]-L-lysine36 + 2 succinate + 2 formaldehyde + 2 CO2
the effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15Ink4b as loss of p15Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells
-
-
?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
protein C/EBPalpha-N6,N6-dimethyl-L-lysine + 2-oxoglutarate + O2
protein C/EBPalpha-N6-methyl-L-lysine + succinate + formaldehyde + CO2
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-
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-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
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?
[histone H3]-N6-methyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-L-lysine 36 + succinate + formaldehyde + CO2
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?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
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?
histone H3-N6,N6-dimethyl-L-lysine36 + 2-oxoglutarate + O2
histone H3-N6-methyl-L-lysine36 + succinate + formaldehyde + CO2
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Jhdm1a is a histone demethylase that specifically demethylates dimethylated H3K36
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?
additional information
?
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substrate specificity of Jhdm1b in vivo using HEK293 cells overexpressing the enzyme, overview
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?
additional information
?
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substrate specificity of Jhdm1b in vivo using HEK293 cells overexpressing the enzyme, overview
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?
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
malfunction
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
additional information
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
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
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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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
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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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
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
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
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). KDM2B_MOUSE
1309
0
149733
Swiss-Prot
other Location (Reliability: 1)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
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Jhdm1a knockdown or scramble adenoviruses are transduced into the liver of wild-type male C57BL/6J mice
additional information
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Ndy1 knockdown by siRNA in fibroblasts. Significant reduction in K36-dimethylated histone H3 associated with the promoters of Nqo1 and Prdx4 genes in cells engineered to overexpress Ndy1 but not its CXXC deletion mutant. Trimethylation of histone H3 at K4 is also reduced in the promoter regions of both genes, though in a spatially restricted manner that spared the region near the transcription start site. But the effect of Ndy1 on histone H3K4 trimethylation is weak
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression analysis by quantitative reverse transcriptase PCR, overexpression of wild-type Jhdm1b in HeLa and HEK293 cells
ectopic expression of either wild-type Jhdm1a or H212A point mutant in the liver of diabetic ob/ob mice
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gene Jmjd5, FLAG-His6 tagged mutant H319A is cloned into the pDON-5 Neo plasmid to produce retroviruses, shRNA-expressing retroviruses are used for silencing of the enzyme, expression of C-terminally His-tagged JMJD5 in Escherichia coli, quantitative reverse transcription PCR expression analysis
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recombinant Ndy1 overexpression in mouse embryonic fibroblasts, quantitative real-time reverse transcriptase PCR expression analysis
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
knockdown of Jhdm1b in primary mouse embryonic fibroblasts inhibits cell proliferation and induces cellular senescence in a pRb and p53 pathway-dependent manner. The effect of Jhdm1b on cell proliferation and cellular senescence is mediated through de-repression of p15Ink4b as loss of p15Ink4b function rescues cell proliferation defects in Jhdm1b knockdown cells
mRNA and protein levels of Jmjd2a are significantly increased in the neurons of mouse undergoing neuropathic pain
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
He, J.; Kallin, E.M.; Tsukada, Y.; Zhang, Y.
The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b)
Nat. Struct. Mol. Biol.
15
1169-1175
2008
Mus musculus (Q6P1G2), Mus musculus
Ishimura, A.; Minehata, K.; Terashima, M.; Kondoh, G.; Hara, T.; Suzuki, T.
Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression
Development
139
749-759
2012
Mus musculus
Pan, D.; Mao, C.; Zou, T.; Yao, A.Y.; Cooper, M.P.; Boyartchuk, V.; Wang, Y.X.
The histone demethylase Jhdm1a regulates hepatic gluconeogenesis
PLoS Genet.
8
e1002761
2012
Homo sapiens, Mus musculus, Mus musculus C57/BL6J
Polytarchou, C.; Pfau, R.; Hatziapostolou, M.; Tsichlis, P.
The JmjC domain histone demethylase Ndy1 regulates redox homeostasis and protects cells from oxidative stress
Mol. Cell. Biol.
28
7451-7464
2008
Mus musculus
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
Turberfield, A.H.; Kondo, T.; Nakayama, M.; Koseki, Y.; King, H.W.; Koseki, H.; Klose, R.J.
KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity
Nucleic Acids Res.
47
9005-9023
2019
Mus musculus (P59997), Mus musculus (Q6P1G2)
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