{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9HAZ2","secondaryAccessions":["A6NHQ8","B1AJP7","B1AJP8","B1AJP9","B1WB48","Q8WYJ9","Q9C0I8"],"uniProtkbId":"PRD16_HUMAN","entryAudit":{"firstPublicDate":"2001-11-16","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2009-09-22","entryVersion":217,"sequenceVersion":3},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Histone-lysine N-methyltransferase PRDM16"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}],"value":"2.1.1.367"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"PR domain zinc finger protein 16"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"PR domain-containing protein 16"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Transcription factor MEL1"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11050005"}],"value":"MDS1/EVI1-like gene 1"}]}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"22939622"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:14000"}],"value":"PRDM16"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000312","source":"EMBL","id":"BAB21766.2"}],"value":"KIAA1675"},{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"11050005"}],"value":"MEL1"},{"value":"PFM13"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12816872"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19049980"}],"value":"Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context (PubMed:12816872). In the cytoplasm, acts as a histone methyltransferase, which catalyzes monomethylation of 'Lys-9' of free histone H3 (H3K9me1) during translation (By similarity). Monomethylated histone H3 is then transported to the nucleus and incorporated into nucleosomes where SUV39H methyltransferases (SUV39H1 and SUV39H2) use it as a substrate to catalyze histone H3 'Lys-9' trimethylation (H3K9me3) (By similarity). Probably one of the primary histone methyltransferases along with MECOM/PRDM3 that direct cytoplasmic H3K9me1 methylation (By similarity). In the nucleus, acts as a key chromatin adapter that mediates differentiation of brown and beige adipocytes, which are specialized in dissipating chemical energy in the form of heat in response to cold or excess feeding (By similarity). Following recruitment to chromatin by PPARG nuclear receptor, promotes differentiation of myoblastic precursors into brown adipose cells (By similarity). Mechanistically, acts by mediating recruitment of (1) EHMT1 histone methyltransferase, thereby inhibiting the expression of white adipose-selective genes or (2) mediator complex, activating genes that are highly expressed in brown adipocytes, such as UCP1, PPARA, and PPARGC1A (By similarity). Also mediates differentiation of beige adipocytes from white adipose cells following recruitment by PPARG (By similarity). In addition to adipocyte differentiation, also involved in tolerance to gut microbiota: following recruitment to chromatin by RORgammaT (RORC) in a subset of antigen-presenting cells, promotes differentiation of peripherally-induced regulatory T-cells (pTreg), which suppress inflammatory responses to commensal microorganisms (By similarity). Also required in adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age (By similarity). Functions as a repressor of TGF-beta signaling (PubMed:19049980)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12816872"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14656887"}],"value":"Binds DNA and functions as a transcriptional regulator (PubMed:12816872). Functions as a repressor of TGF-beta signaling (PubMed:14656887). May regulate granulocyte differentiation (PubMed:12816872)"}],"commentType":"FUNCTION","molecule":"Isoform 4"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"L-lysyl(9)-[histone H3] + S-adenosyl-L-methionine = N(6)-methyl-L-lysyl(9)-[histone H3] + S-adenosyl-L-homocysteine + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:60280"},{"database":"Rhea","id":"RHEA-COMP:15542"},{"database":"Rhea","id":"RHEA-COMP:15546"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:29969"},{"database":"ChEBI","id":"CHEBI:57856"},{"database":"ChEBI","id":"CHEBI:59789"},{"database":"ChEBI","id":"CHEBI:61929"}],"ecNumber":"2.1.1.367","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:60281"},"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19049980"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25578880"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30462309"}],"value":"Interacts with CEBPA, CEBPB and CEBPD; the interaction is direct (By similarity). Interacts with PPARG; controls brown adipocytes (By similarity). Interacts with CTBP1 and CTBP2; represses the expression of white adipose tissue-specific genes (By similarity). Interacts (via N-terminus) with RBBP4 (PubMed:30462309). Interacts with PPARGC1A and PPARGC1B; interaction with PPARGC1A or PPARGC1B activates the transcription of brown adipose tissue-specific gene (By similarity). Interacts with HDAC1, SKI and SMAD2; the interaction with SKI promotes the recruitment of SMAD3-HDAC1 complex on the promoter of TGF-beta target genes (PubMed:19049980). Interacts with ZNF516; the interaction is direct and may play a role in the transcription of brown adipose tissue-specific gene (PubMed:25578880). Interacts with EHMT1; promoting PRDM16 stability by preventing its ubiquitination and degradation (By similarity). Interacts with MED1; promoting recruitment of the mediator complex (By similarity). Interacts with TLE3; preventing association between PRDM16 and PPARG and differentiation into brown adipose cells (By similarity). Interacts (when phosphorylated) with PIN1; promoting PRDM16 degradation (By similarity). Interacts with DHRS7B; preventing association between PRDM16 and PPARG and differentiation into brown adipose cells (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q9HAZ2","intActId":"EBI-2795620"},"interactantTwo":{"uniProtKBAccession":"Q09028","geneName":"RBBP4","intActId":"EBI-620823"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9HAZ2-2","intActId":"EBI-5282871"},"interactantTwo":{"uniProtKBAccession":"P56546","geneName":"Ctbp2","intActId":"EBI-1384883"},"numberOfExperiments":2,"organismDiffer":true},{"interactantOne":{"uniProtKBAccession":"Q9HAZ2-4","intActId":"EBI-4566658"},"interactantTwo":{"uniProtKBAccession":"P56546","geneName":"Ctbp2","intActId":"EBI-1384883"},"numberOfExperiments":2,"organismDiffer":true}]},{"commentType":"SUBCELLULAR LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19049980"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}],"value":"Chromosome","id":"SL-0468"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22939622"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative promoter usage","Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q9HAZ2-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"synonyms":[{"value":"MEL1L"}],"isoformIds":["Q9HAZ2-2"],"sequenceIds":["VSP_006932"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["Q9HAZ2-3"],"sequenceIds":["VSP_038064","VSP_038065"],"isoformSequenceStatus":"Described"},{"name":{"value":"4"},"synonyms":[{"value":"MEL1S"}],"isoformIds":["Q9HAZ2-4"],"sequenceIds":["VSP_038063"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11050005"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12816872"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23768516"}],"value":"Expressed in uterus and kidney. Expressed in both cardiomyocytes and interstitial cells"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}],"value":"Acetylation at Lys-915 py EP300/p300 abolishes its association with PPARG and ability to promote differentiation of brown adipocytes. Deacetylated by HDAC6"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}],"value":"Phosphorylated; phosphorylation promotes interaction with PIN1 and degradation"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}],"value":"Ubiquitinated by the CRL2(APPBP2) complex, leading to its degradation by the proteasome. Interaction with EHMT1 promotes PRDM16 stability by preventing interaction with APPBP2 and subsequent ubiquitination"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"A2A935"}],"value":"Sumoylated by CBX4, promoting its stabilization by preventing PRDM16 ubiquitination and degradation"}],"commentType":"PTM"},{"commentType":"DISEASE","disease":{"diseaseId":"Left ventricular non-compaction 8","diseaseAccession":"DI-03859","acronym":"LVNC8","description":"A form of left ventricular non-compaction, a cardiomyopathy due to myocardial morphogenesis arrest and characterized by a hypertrophic left ventricle, a severely thickened 2-layered myocardium, numerous prominent trabeculations, deep intertrabecular recesses, and poor systolic function. Clinical manifestations are variable. Some affected individuals experience no symptoms at all, others develop heart failure. In some cases, left ventricular non-compaction is associated with other congenital heart anomalies. LVNC8 is an autosomal dominant condition.","diseaseCrossReference":{"database":"MIM","id":"615373"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23768516"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Cardiomyopathy, dilated, 1LL","diseaseAccession":"DI-03860","acronym":"CMD1LL","description":"A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. 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Isoform 4 is specifically expressed in adult T-cell leukemia"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Produced by alternative promoter usage"}],"commentType":"MISCELLANEOUS","molecule":"Isoform 4"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the PRDM16 family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"BAB21766.2","note":"Extended N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"WEB RESOURCE","resourceName":"Atlas of Genetics and Cytogenetics in Oncology and Haematology","resourceUrl":"https://atlasgeneticsoncology.org/gene/408/PRDM16MEL1","ftp":false}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":1276,"modifier":"EXACT"}},"description":"Histone-lysine N-methyltransferase 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