UniProt functional annotation for O60341



	UniProt functional annotation for O60341

UniProt code: O60341.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Histone demethylase that can demethylate both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context (PubMed:15620353, PubMed:15811342, PubMed:16140033, PubMed:16079794, PubMed:16079795, PubMed:16223729). Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed (PubMed:15620353, PubMed:15811342, PubMed:16079794, PubMed:21300290). Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me (PubMed:15620353, PubMed:20389281, PubMed:21300290, PubMed:23721412). May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity (PubMed:16140033, PubMed:16079794, PubMed:16885027, PubMed:21300290, PubMed:23721412). Also acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in AR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A (PubMed:16079795). Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7 (PubMed:20389281). {ECO:0000269|PubMed:12032298, ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:15811342, ECO:0000269|PubMed:16079794, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:16140033, ECO:0000269|PubMed:16223729, ECO:0000269|PubMed:16885027, ECO:0000269|PubMed:16956976, ECO:0000269|PubMed:17805299, ECO:0000269|PubMed:20228790, ECO:0000269|PubMed:20389281, ECO:0000269|PubMed:20562920, ECO:0000269|PubMed:21300290, ECO:0000269|PubMed:23721412}.

Catalytic activity: Reaction=2 A + 2 H2O + N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] = 2 AH2 + 2 formaldehyde + L-lysyl(4)-[histone H3]; Xref=Rhea:RHEA:60244, Rhea:RHEA-COMP:15540, Rhea:RHEA-COMP:15547, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377, ChEBI:CHEBI:16842, ChEBI:CHEBI:17499, ChEBI:CHEBI:29969, ChEBI:CHEBI:61976; EC=1.14.99.66; Evidence={ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:15811342};

Cofactor: Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:15811342, ECO:0000269|PubMed:16956976, ECO:0000269|PubMed:21300290, ECO:0000269|PubMed:23721412};

Activity regulation: The N-terminal sequences of INSM1 and SNAI1 compete with histone H3 for the same binding site and thereby inhibit histone demethylation (in vitro). {ECO:0000269|PubMed:21300290, ECO:0000269|PubMed:23721412}.

Biophysicochemical properties: Kinetic parameters: KM=3.0 uM for H3 monomethyl-K4 {ECO:0000269|PubMed:16223729}; KM=4.2 uM for H3 dimethyl-K4 {ECO:0000269|PubMed:16223729}; KM=3.9 uM for H3 monomethyl-K4-monomethyl-K9 {ECO:0000269|PubMed:16223729}; KM=17.5 uM for monomethyl-K4-acetyl-K9 {ECO:0000269|PubMed:16223729};

Subunit: Component of a histone demethylase complex with RCOR1 (PubMed:20389281, PubMed:23721412, PubMed:16885027, PubMed:21300290). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:12032298, PubMed:11102443). Interacts directly with GFI1 and GFI1B. Interacts with INSM1 (via N-terminus) (PubMed:23721412). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763, PubMed:16140033, PubMed:16885027). In the complex, RCOR1/CoREST strongly enhances the demethylase activity and protects it from the proteasome while PHF21A/BHC80 inhibits the demethylase activity (PubMed:16079794, PubMed:16956976). Interacts with the androgen receptor (AR) (PubMed:16079795). Interacts with SNAI1 (via SNAG domain) (PubMed:20389281, PubMed:20562920, PubMed:21300290, PubMed:23721412). Interacts (via AOD/Tower domain) with JADE2 (via C-terminus) (PubMed:25018020). Interacts with ESRRB; co-occupes the core set of ESRRB targets (By similarity). {ECO:0000250|UniProtKB:Q6ZQ88, ECO:0000269|PubMed:11102443, ECO:0000269|PubMed:12032298, ECO:0000269|PubMed:12493763, ECO:0000269|PubMed:16079794, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:16140033, ECO:0000269|PubMed:16885027, ECO:0000269|PubMed:16956976, ECO:0000269|PubMed:20389281, ECO:0000269|PubMed:20562920, ECO:0000269|PubMed:21300290, ECO:0000269|PubMed:23721412, ECO:0000269|PubMed:25018020}.

Subcellular location: Nucleus {ECO:0000269|PubMed:11102443, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:20389281}.

Tissue specificity: Ubiquitously expressed. {ECO:0000269|PubMed:16079795}.

Induction: Down-regulated during neural differentiation in neuroblastoma cancer. {ECO:0000269|PubMed:25018020}.

Domain: The SWIRM domain may act as an anchor site for a histone tail. {ECO:0000269|PubMed:16531230}.

Ptm: Polyubiquitinated by JADE2; which leads to its proteasomal degradation. {ECO:0000269|PubMed:25018020}.

Disease: Cleft palate, psychomotor retardation, and distinctive facial features (CPRF) [MIM:616728]: A syndrome characterized by cleft palate, developmental delay, psychomotor retardation, and facial dysmorphic features including a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and widely spaced teeth. Cleft palate is a congenital fissure of the soft and/or hard palate, due to faulty fusion. {ECO:0000269|PubMed:23020937, ECO:0000269|PubMed:24838796, ECO:0000269|PubMed:26656649}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the flavin monoamine oxidase family. {ECO:0000305}.

Sequence caution: Sequence=BAA25527.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Histone demethylase that can demethylate both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context (PubMed:15620353, PubMed:15811342, PubMed:16140033, PubMed:16079794, PubMed:16079795, PubMed:16223729). Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed (PubMed:15620353, PubMed:15811342, PubMed:16079794, PubMed:21300290). Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me (PubMed:15620353, PubMed:20389281, PubMed:21300290, PubMed:23721412). May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity (PubMed:16140033, PubMed:16079794, PubMed:16885027, PubMed:21300290, PubMed:23721412). Also acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in AR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A (PubMed:16079795). Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7 (PubMed:20389281). {ECO:0000269\|PubMed:12032298, ECO:0000269\|PubMed:15620353, ECO:0000269\|PubMed:15811342, ECO:0000269\|PubMed:16079794, ECO:0000269\|PubMed:16079795, ECO:0000269\|PubMed:16140033, ECO:0000269\|PubMed:16223729, ECO:0000269\|PubMed:16885027, ECO:0000269\|PubMed:16956976, ECO:0000269\|PubMed:17805299, ECO:0000269\|PubMed:20228790, ECO:0000269\|PubMed:20389281, ECO:0000269\|PubMed:20562920, ECO:0000269\|PubMed:21300290, ECO:0000269\|PubMed:23721412}.


Catalytic activity:		Reaction=2 A + 2 H2O + N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] = 2 AH2 + 2 formaldehyde + L-lysyl(4)-[histone H3]; Xref=Rhea:RHEA:60244, Rhea:RHEA-COMP:15540, Rhea:RHEA-COMP:15547, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377, ChEBI:CHEBI:16842, ChEBI:CHEBI:17499, ChEBI:CHEBI:29969, ChEBI:CHEBI:61976; EC=1.14.99.66; Evidence={ECO:0000269\|PubMed:15620353, ECO:0000269\|PubMed:15811342};
Cofactor:		Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000269\|PubMed:15620353, ECO:0000269\|PubMed:15811342, ECO:0000269\|PubMed:16956976, ECO:0000269\|PubMed:21300290, ECO:0000269\|PubMed:23721412};
Activity regulation:		The N-terminal sequences of INSM1 and SNAI1 compete with histone H3 for the same binding site and thereby inhibit histone demethylation (in vitro). {ECO:0000269\|PubMed:21300290, ECO:0000269\|PubMed:23721412}.
Biophysicochemical properties:		Kinetic parameters: KM=3.0 uM for H3 monomethyl-K4 {ECO:0000269\|PubMed:16223729}; KM=4.2 uM for H3 dimethyl-K4 {ECO:0000269\|PubMed:16223729}; KM=3.9 uM for H3 monomethyl-K4-monomethyl-K9 {ECO:0000269\|PubMed:16223729}; KM=17.5 uM for monomethyl-K4-acetyl-K9 {ECO:0000269\|PubMed:16223729};
Subunit:		Component of a histone demethylase complex with RCOR1 (PubMed:20389281, PubMed:23721412, PubMed:16885027, PubMed:21300290). Component of a RCOR/GFI/KDM1A/HDAC complex (PubMed:12032298, PubMed:11102443). Interacts directly with GFI1 and GFI1B. Interacts with INSM1 (via N-terminus) (PubMed:23721412). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763, PubMed:16140033, PubMed:16885027). In the complex, RCOR1/CoREST strongly enhances the demethylase activity and protects it from the proteasome while PHF21A/BHC80 inhibits the demethylase activity (PubMed:16079794, PubMed:16956976). Interacts with the androgen receptor (AR) (PubMed:16079795). Interacts with SNAI1 (via SNAG domain) (PubMed:20389281, PubMed:20562920, PubMed:21300290, PubMed:23721412). Interacts (via AOD/Tower domain) with JADE2 (via C-terminus) (PubMed:25018020). Interacts with ESRRB; co-occupes the core set of ESRRB targets (By similarity). {ECO:0000250\|UniProtKB:Q6ZQ88, ECO:0000269\|PubMed:11102443, ECO:0000269\|PubMed:12032298, ECO:0000269\|PubMed:12493763, ECO:0000269\|PubMed:16079794, ECO:0000269\|PubMed:16079795, ECO:0000269\|PubMed:16140033, ECO:0000269\|PubMed:16885027, ECO:0000269\|PubMed:16956976, ECO:0000269\|PubMed:20389281, ECO:0000269\|PubMed:20562920, ECO:0000269\|PubMed:21300290, ECO:0000269\|PubMed:23721412, ECO:0000269\|PubMed:25018020}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:11102443, ECO:0000269\|PubMed:16079795, ECO:0000269\|PubMed:20389281}.
Tissue specificity:		Ubiquitously expressed. {ECO:0000269\|PubMed:16079795}.
Induction:		Down-regulated during neural differentiation in neuroblastoma cancer. {ECO:0000269\|PubMed:25018020}.
Domain:		The SWIRM domain may act as an anchor site for a histone tail. {ECO:0000269\|PubMed:16531230}.
Ptm:		Polyubiquitinated by JADE2; which leads to its proteasomal degradation. {ECO:0000269\|PubMed:25018020}.
Disease:		Cleft palate, psychomotor retardation, and distinctive facial features (CPRF) [MIM:616728]: A syndrome characterized by cleft palate, developmental delay, psychomotor retardation, and facial dysmorphic features including a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and widely spaced teeth. Cleft palate is a congenital fissure of the soft and/or hard palate, due to faulty fusion. {ECO:0000269\|PubMed:23020937, ECO:0000269\|PubMed:24838796, ECO:0000269\|PubMed:26656649}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the flavin monoamine oxidase family. {ECO:0000305}.
Sequence caution:		Sequence=BAA25527.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};