SETD4_MOUSE
ID SETD4_MOUSE Reviewed; 439 AA.
AC P58467; G3X9W6;
DT 13-DEC-2001, integrated into UniProtKB/Swiss-Prot.
DT 03-JUL-2019, sequence version 2.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=SET domain-containing protein 4 {ECO:0000305};
DE EC=2.1.1.- {ECO:0000250|UniProtKB:Q9NVD3};
DE EC=2.1.1.364 {ECO:0000269|PubMed:31376731};
GN Name=Setd4 {ECO:0000303|PubMed:31376731, ECO:0000312|MGI:MGI:2136890};
GN Synonyms=ORF21 {ECO:0000303|PubMed:11707072};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11707072; DOI=10.1006/geno.2001.6640;
RA Reymond A., Friedli M., Neergaard Henrichsen C., Chapot F., Deutsch S.,
RA Ucla C., Rossier C., Lyle R., Guipponi M., Antonarakis S.E.;
RT "From PREDs and open reading frames to cDNA isolation: revisiting the human
RT chromosome 21 transcription map.";
RL Genomics 78:46-54(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=31376731; DOI=10.1016/j.molimm.2019.07.011;
RA Zhong Y., Ye P., Mei Z., Huang S., Huang M., Li Y., Niu S., Zhao S.,
RA Cai J., Wang J., Zou H., Jiang Y., Liu J.;
RT "The novel methyltransferase SETD4 regulates TLR agonist-induced expression
RT of cytokines through methylation of lysine 4 at histone 3 in macrophages.";
RL Mol. Immunol. 114:179-188(2019).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=31794893; DOI=10.1016/j.dnarep.2019.102754;
RA Feng X., Lu H., Yue J., Schneider N., Liu J., Denzin L.K., Chan C.S.,
RA De S., Shen Z.;
RT "Loss of Setd4 delays radiation-induced thymic lymphoma in mice.";
RL DNA Repair 86:102754-102754(2020).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=32259569; DOI=10.1016/j.ijrobp.2020.03.026;
RA Feng X., Lu H., Yue J., Shettigar M., Liu J., Denzin L.K., Shen Z.;
RT "Deletion of mouse Setd4 promotes the recovery of hematopoietic failure.";
RL Int. J. Radiat. Oncol. Biol. Phys. 107:779-792(2020).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=33506343; DOI=10.1007/s12015-021-10121-1;
RA Liao X., Wu C., Shao Z., Zhang S., Zou Y., Wang K., Ha Y., Xing J.,
RA Zheng A., Shen Z., Zheng S., Guo J., Jie W.;
RT "SETD4 in the proliferation, migration, angiogenesis, myogenic
RT differentiation and genomic methylation of bone marrow mesenchymal stem
RT cells.";
RL Stem. Cell. Rev. Rep. 17:1374-1389(2021).
CC -!- FUNCTION: Histone-lysine N-methyltransferase that acts as a regulator
CC of cell proliferation, cell differentiation and inflammatory response
CC (PubMed:31376731, PubMed:31794893, PubMed:33506343). Regulates the
CC inflammatory response by mediating mono- and dimethylation of 'Lys-4'
CC of histone H3 (H3K4me1 and H3K4me2, respectively), leading to activate
CC the transcription of pro-inflammatory cytokines IL6 and TNF-alpha
CC (PubMed:31376731). Also involved in the regulation of stem cell
CC quiescence by catalyzing the trimethylation of 'Lys-20' of histone H4
CC (H4K20me3), thereby promoting heterochromatin formation (By
CC similarity). Involved in proliferation, migration, paracrine and
CC myogenic differentiation of bone marrow mesenchymal stem cells (BMSCs)
CC (PubMed:33506343). {ECO:0000250|UniProtKB:Q9NVD3,
CC ECO:0000269|PubMed:31376731, ECO:0000269|PubMed:31794893,
CC ECO:0000269|PubMed:33506343}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = H(+) +
CC N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:60264, Rhea:RHEA-COMP:15543, Rhea:RHEA-COMP:15547,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61929; EC=2.1.1.364;
CC Evidence={ECO:0000269|PubMed:31376731};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine
CC = H(+) + N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:60268, Rhea:RHEA-COMP:15540, Rhea:RHEA-
CC COMP:15543, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:61929, ChEBI:CHEBI:61976;
CC Evidence={ECO:0000269|PubMed:31376731};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine = H(+) +
CC N(6)-methyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:60344, Rhea:RHEA-COMP:15554, Rhea:RHEA-COMP:15555,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61929;
CC Evidence={ECO:0000250|UniProtKB:Q9NVD3};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N(6)-methyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-methionine
CC = H(+) + N(6),N(6)-dimethyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:60348, Rhea:RHEA-COMP:15555, Rhea:RHEA-
CC COMP:15556, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:61929, ChEBI:CHEBI:61976;
CC Evidence={ECO:0000250|UniProtKB:Q9NVD3};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=N(6),N(6)-dimethyl-L-lysyl(20)-[histone H4] + S-adenosyl-L-
CC methionine = H(+) + N(6),N(6),N(6)-trimethyl-L-lysyl(20)-[histone H4]
CC + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:61992, Rhea:RHEA-
CC COMP:15556, Rhea:RHEA-COMP:15998, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:61961,
CC ChEBI:CHEBI:61976; Evidence={ECO:0000250|UniProtKB:Q9NVD3};
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:31376731}.
CC Nucleus {ECO:0000269|PubMed:31376731}.
CC -!- DISRUPTION PHENOTYPE: No visible phenotype in normal physiological
CC conditions (PubMed:33506343). Increased proliferation of bone marrow
CC mesenchymal stem cells (BMSCs), impaired BMSCs migration and
CC differentiation potentials of lineages of cardiacmyocyte and smooth
CC muscle cell (PubMed:33506343). Conditional deletion in adult mice
CC improves the survival from radiation-induced hematopoietic failure and
CC thymic lymphoma (PubMed:31794893, PubMed:32259569). Extends survival
CC from radiation-induced thymic lymphoma is likely due to slower tumor
CC enlargement in the thymus (PubMed:31794893).
CC {ECO:0000269|PubMed:31794893, ECO:0000269|PubMed:32259569,
CC ECO:0000269|PubMed:33506343}.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding methyltransferase
CC superfamily. SETD4 family. {ECO:0000255|PROSITE-ProRule:PRU00190,
CC ECO:0000305}.
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DR EMBL; AY037804; AAK68849.1; -; mRNA.
DR EMBL; AC160993; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466602; EDL03771.1; -; Genomic_DNA.
DR CCDS; CCDS28340.1; -.
DR RefSeq; NP_663457.2; NM_145482.3.
DR RefSeq; XP_006523078.1; XM_006523015.3.
DR RefSeq; XP_006523079.1; XM_006523016.3.
DR RefSeq; XP_006523080.1; XM_006523017.3.
DR RefSeq; XP_006523081.1; XM_006523018.3.
DR AlphaFoldDB; P58467; -.
DR SMR; P58467; -.
DR STRING; 10090.ENSMUSP00000109584; -.
DR PhosphoSitePlus; P58467; -.
DR PaxDb; P58467; -.
DR PRIDE; P58467; -.
DR Antibodypedia; 8172; 120 antibodies from 20 providers.
DR DNASU; 224440; -.
DR Ensembl; ENSMUST00000023669; ENSMUSP00000023669; ENSMUSG00000022948.
DR Ensembl; ENSMUST00000233931; ENSMUSP00000156723; ENSMUSG00000022948.
DR GeneID; 224440; -.
DR KEGG; mmu:224440; -.
DR UCSC; uc007zzq.2; mouse.
DR CTD; 54093; -.
DR MGI; MGI:2136890; Setd4.
DR VEuPathDB; HostDB:ENSMUSG00000022948; -.
DR eggNOG; KOG1337; Eukaryota.
DR GeneTree; ENSGT00940000153577; -.
DR HOGENOM; CLU_029120_3_0_1; -.
DR InParanoid; P58467; -.
DR OMA; ADEFTCW; -.
DR OrthoDB; 1209399at2759; -.
DR PhylomeDB; P58467; -.
DR TreeFam; TF106421; -.
DR BioGRID-ORCS; 224440; 3 hits in 74 CRISPR screens.
DR ChiTaRS; Setd4; mouse.
DR PRO; PR:P58467; -.
DR Proteomes; UP000000589; Chromosome 16.
DR RNAct; P58467; protein.
DR Bgee; ENSMUSG00000022948; Expressed in primary oocyte and 242 other tissues.
DR ExpressionAtlas; P58467; baseline and differential.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0042800; F:histone methyltransferase activity (H3-K4 specific); IDA:UniProtKB.
DR GO; GO:0042799; F:histone methyltransferase activity (H4-K20 specific); ISS:UniProtKB.
DR GO; GO:0016279; F:protein-lysine N-methyltransferase activity; IBA:GO_Central.
DR GO; GO:0044648; P:histone H3-K4 dimethylation; IDA:UniProtKB.
DR GO; GO:0097692; P:histone H3-K4 monomethylation; IDA:UniProtKB.
DR GO; GO:0034773; P:histone H4-K20 trimethylation; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0018026; P:peptidyl-lysine monomethylation; IBA:GO_Central.
DR GO; GO:0018023; P:peptidyl-lysine trimethylation; IBA:GO_Central.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:UniProtKB.
DR GO; GO:0071863; P:regulation of cell proliferation in bone marrow; IMP:UniProtKB.
DR CDD; cd19177; SET_SETD4; 1.
DR Gene3D; 3.90.1420.10; -; 1.
DR InterPro; IPR015353; Rubisco_LSMT_subst-bd.
DR InterPro; IPR036464; Rubisco_LSMT_subst-bd_sf.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR046341; SET_dom_sf.
DR InterPro; IPR016852; SET_MeTrfase.
DR InterPro; IPR044429; SETD4_SET.
DR Pfam; PF09273; Rubis-subs-bind; 1.
DR Pfam; PF00856; SET; 1.
DR PIRSF; PIRSF027158; Lys_MTase_YDR198C_prd; 1.
DR SUPFAM; SSF82199; SSF82199; 1.
DR PROSITE; PS50280; SET; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Inflammatory response; Methyltransferase; Nucleus;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..439
FT /note="SET domain-containing protein 4"
FT /id="PRO_0000079510"
FT DOMAIN 47..272
FT /note="SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT REGION 1..25
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..19
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 271
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT CONFLICT 408
FT /note="S -> N (in Ref. 2; AAK68849)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 439 AA; 49810 MW; BC4FF50A203ADD21 CRC64;
MQRRRGRTER ARKRRRRSSG SRAVNESYRS EFIELRKWLK ERKFEDTDLV PASFPGTGRG
LMSKASLQEG QVMISLPESC LLTTDTVIRS SLGPYIKKWK PPVSPLLALC TFLVSEKHAG
CRSLWKSYLD ILPKSYTCPV CLEPEVVDLL PSPLKAKAEE QRARVQDLFT SARGFFSTLQ
PLFAEPVDSV FSYRAFLWAW CTVNTRAVYL RSRRQECLSA EPDTCALAPF LDLLNHSPHV
QVKAAFNEKT RCYEIRTASR CRKHQEVFIC YGPHDNQRLL LEYGFVSVRN PHACVPVSAD
MLVKFLPAAD KQLHRKITIL KDHGFTGNLT FGWDGPSWRL LTALKLLCLE AERFTSWKKV
LLGEVISDTN EKTSLGVAQK ICSDVIEETH AVLRKVSDMK EGTVSLRSQL SLVEALRMEE
LRILQASAEI LSGLLAPFS
