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MEF2D (myocyte enhancer factor 2D)

Written2009-10Victor Prima, Lyudmyla G Glushakova, Stephen P Hunger
University of Florida College of Medicine, Gainesville, FL 32610, USA (VP, LGG); Children's Hospital, the Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (SPH)

(Note : for Links provided by Atlas : click)

Identity

Other aliasDKFZp686I1536
HGNC (Hugo) MEF2D
LocusID (NCBI) 4209
Atlas_Id 43636
Location 1q22  [Link to chromosome band 1q22]
Location_base_pair Starts at 156463721 and ends at 156490599 bp from pter ( according to hg19-Feb_2009)  [Mapping MEF2D.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DAZAP1 (19p13.3) / MEF2D (1q22)FOXJ2 (12p13.31) / MEF2D (1q22)LZTS3 (20p13) / MEF2D (1q22)
MEF2D (1q22) / BCL9 (1q21.2)MEF2D (1q22) / DAZAP1 (19p13.3)MEF2D (1q22) / FOXJ2 (12p13.31)
MEF2D (1q22) / HNRNPUL1 (19q13.2)MEF2D (1q22) / P2RX1 (17p13.2)MEF2D (1q22) / SS18 (18q11.2)
MEF2D (1q22) / STAT6 (12q13.3)MEF2D (1q22) / ZDHHC5 (11q12.1)SS18 (18q11.2) / MEF2D (1q22)
Note MEF2D is a member of the family of myocyte enhancer factor MEF2 that includes MEF2A, MEF2B, MEF2D, MEF2C.

DNA/RNA

Description 12 exons.
Transcription 5888bp mRNA, coding sequence: from 391bp to 1956bp (NCBI, GenBank NM_005920); alternative splicing in E3 (3alpha1 and 3alpha2) and beta produces 4 splicing isoforms: alpha1, alpha1beta, alpha2, alpha2beta (Zhu et al., 2005).

Protein

Note MEF2D belongs to MEF2 (myocyte enhancer factor 2)-like/Type II subfamily of MADS (MCM1, Agamous, Deficiens, and SRF (serum response factor) box family of eukaryotic transcriptional regulators).
Description MEF2D encodes approximately a 521 aa-long protein (GenBank at NCBI presented 4 isoforms: CRA_a, 521 aa, EAW52952.1; CRA_b, 143 aa, EAW52949.1; CRA_c, 288 aa, EAW52950.1; CRA_d, 523 aa, EAW52951.1). It is composed of several domains: the MADS-box on N terminus (2-78 aa, MAD MEF2 like); the 29-aa MEF2 domain immediately C-terminal to the MADS- box (unique to the MEF2 factors); C-terminal transcriptional activation domains. Both MADS and MEF2 domains are necessary and sufficient for dimerization and binding to the DNA sequence CTA(A/T)4TAG/A. MEF2 domain influences cofactor interactions. (Pollock and Treisman, 1991; Molkentin and Olson, 1996). Regions: 2-38 aa of the MADS domain confer DNA binding site specificity; 21-73 aa, dimerization interface; 59 aa, putative phosphorylation site.
Expression High level expression in muscles and neurons, at lower levels in a wide range of cell types (Black and Olson, 1998).
Localisation Nuclear (Neely et al., 2009).
Function DNA binding, transcriptional activation. Transmission of extracellular signals to the genome, control of cell differentiation, proliferation, morphogenesis, survival and apoptosis of a wide range of cell types. Important in immediate-early development in animals. MEF2D dimers regulate expression of genes involved in muscle-specific and/or growth factor-related transcription.
It seems to be transcriptional effector of mitogenic signaling pathways initiated by mitogen-activated protein kinases (MAPKs) including p38 and ERK5 (extracellular signal-related kinase 5)/Big MAPK-1, and also plays critical roles in calcium-regulated signaling pathways that control survival of neurons and T-cells; induces expression of c-jun, a known transforming oncogene, and has recently been identified in murine retroviral mutagenesis studies as a candidate oncogene involved in the pathogenesis of lymphoid malignancies. (Lund et al., 2002; Suzuki et al., 2002; Han and Prywes, 1995).
Homology Belongs to MEF2-like/Type II subfamily of MADS box family of eukaryotic transcriptional regulators. The MADS-box is found so far in a diverse group of transcription factors from yeast, animals and seed plants.

Implicated in

Note
  
Entity Acute lymphoblastic leukemia (ALL)
Hybrid/Mutated Gene A variant t(1;19)(q23;p13.3) 1048 translocation creates reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1 fusion genes that are expressed in acute lymphoblastic leukemia (ALL).
DAZAP1 is expressed most abundantly in the testis and mapped to 19p13.3. DAZAP1 is fused to MEF2D by the t(1;19); the genomic breakpoints occur in introns of MEF2D and DAZAP1 (der(1) (Genbank accession AY681493) and der(19) (accession AY681494)). der(19) breakpoint is located within the 1500 kilobases (kb) of DNA telomeric to E2A. Rearrangments are seen only in TS-2 (ALL cell line) establishing that the t(1;19) interrupts the 19p13.3 gene DAZAP1 with the breakpoint region in approximately the middle of the gene. There is a 5 base pairs insertion at the site of genomic fusion on the der(19) that is not derived from either germline chromosome 1 or 19. Homologous breakpoints occur on the der(1) chromosome with a deletion of 97 bp and a 21 bp GC-rich insertion. MEF2D/DAZAP1 and DAZAP1/MEF2D fusion transcripts are expressed in-frame in TS-2 cells in addition to wild-type DAZAP1 and MEF2D transcripts (Prima et al., 2005).
 
A. Localization of TS-2 chromosome 19 breakpoint via FISH. Metaphase FISH was performed using cosmids containing chromosome 19 genomic DNA. Cosmids that hybridize to the der(19) are located centromeric to the chromosome 19 breakpoint (green signal), while cosmids that hybridize to the der(1) are located telomeric to the chromosome 19 breakpoint (red signal). Split signals on both the der(1) and der(19) chromosomes indicate that the chromosome 19 breakpoint is located within the region homologous to the cosmid. B. Alignment of genomic DNA sequences of TS-2 chromosomes. Genomic sequence (accession AY681494) of der(19) aligned with chromosome 19 (gi: 37552371) and 1 (gi: 37549803) genomic contigs. Non- homologous insert shown in bold uppercase. Genomic sequence (accession AY681493) of der(1) aligned with chromosome 19 and 1 genomic contigs. (Prima et al., 2007).
Abnormal Protein In-frame MEF2D/DAZAP1 and DAZAP1/MEF2D fusion transcripts are expressed in TS-2 cell line and define the DNA-, RNA-binding, and transcriptional regulatory properties of the resultant chimeric proteins. Native DAZAP1 (NP_061832) includes two identified RNA recognition motifs (RRM) specified by amino acids 1-87 and 105-190. DAZAP1/MEF2D fusion cDNAs (accession AY678451) are predicted to encode a chimeric protein that contains all of the first DAZAP1 RRM and a truncated portion of the second RRM joined to the carboxy terminal portion of MEF2D that includes the second TAD. Reciprocal MEF2D/DAZAP1 fusion transcripts (accession AY675556) are predicted to encode a chimera that includes the MEF2D MADS-box, MEF2 domain, and the first TAD joined to the carboxy terminus of DAZAP1 including a truncated portion of RRM 2. DAZAP1 bound strongly to poly(U) and poly(G) at 0.1 M NaCl, whereas DAZAP1/MEF2D bound to the same homopolymers to a lesser degree; MEF2D/DAZAP1 retains DNA-binding properties of wild type MEF2D; MEF2D/DAZAP1 is a more potent transcriptional activator than wild type MEF2D. MEF2D-DAZAP1 was co-immunoprecipitated with wild type MEF2D from HEK293 cells, suggesting that the wild type and chimeric MEF2D proteins could form heterodimers and/or associate with one another in a higher order protein complex in vivo. (Yuki et al., 2004).
 
Structural features of wild type and chimeric MEF2D and DAZAP1 proteins. Predicted functional domains of DAZAP1, MEF2D, DAZAP1/MEF2D and MEF2D/DAZAP1 proteins. Arrows indicate predicted protein breakpoints. (RRM- RNA recognition motif; MADS- DNA binding, protein dimerization domain; MEF2- cofactor interactions domain; TAD- transcriptional activation domain). (Prima et al., 2007).
Oncogenesis MEF2D and DAZAP1 fusion proteins were identified as components of novel pathways that contribute to human leukemogenesis. Both MEF2D/DAZAP1 and DAZAP1/MEF2D have oncogenic properties, and co-expression of both fusion proteins is synergistic (Prima and Hunger, 2007).
MEF2D/DAZAP1 might directly activate transcription of genes critical for lymphocyte growth and/or survival such as interleukin-2, a known transcriptional target of MEF2D in T-cells. Alternatively, MEF2D/DAZAP1 could contribute to leukemogenesis via dysregulated activation of MAPK-mediated cell proliferation pathways, analogous to constitutive activation of a growth factor receptor.
  

Bibliography

Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins.
Black BL, Olson EN.
Annu Rev Cell Dev Biol. 1998;14:167-96.
PMID 9891782
 
Regulatory role of MEF2D in serum induction of the c-jun promoter.
Han TH, Prywes R.
Mol Cell Biol. 1995 Jun;15(6):2907-15.
PMID 7760790
 
Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice.
Lund AH, Turner G, Trubetskoy A, Verhoeven E, Wientjens E, Hulsman D, Russell R, DePinho RA, Lenz J, van Lohuizen M.
Nat Genet. 2002 Sep;32(1):160-5. Epub 2002 Aug 19.
PMID 12185367
 
Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors.
Molkentin JD, Olson EN.
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9366-73.
PMID 8790335
 
Localization of myocyte enhancer factor 2 in the rodent forebrain: regionally-specific cytoplasmic expression of MEF2A.
Neely MD, Robert EM, Baucum AJ, Colbran RJ, Muly EC, Deutch AY.
Brain Res. 2009 Jun 5;1274:55-65. Epub 2009 Apr 9.
PMID 19362076
 
Human SRF-related proteins: DNA-binding properties and potential regulatory targets.
Pollock R, Treisman R.
Genes Dev. 1991 Dec;5(12A):2327-41.
PMID 1748287
 
Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia.
Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M, Hunger SP.
Leukemia. 2005 May;19(5):806-13.
PMID 15744350
 
Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia.
Prima V, Hunger SP.
Leukemia. 2007 Dec;21(12):2470-5. Epub 2007 Sep 27.
PMID 17898785
 
New genes involved in cancer identified by retroviral tagging.
Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ, Jenkins NA, Copeland NG.
Nat Genet. 2002 Sep;32(1):166-74. Epub 2002 Aug 19.
PMID 12185365
 
Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t(1;19)(q23;p13).
Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, Inazawa J.
Cancer Sci. 2004 Jun;95(6):503-7.
PMID 15182431
 
Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain.
Zhu B, Ramachandran B, Gulick T.
J Biol Chem. 2005 Aug 5;280(31):28749-60. Epub 2005 Apr 15.
PMID 15834131
 

Citation

This paper should be referenced as such :
Prima, V ; Glushakova, LG ; Hunger, SP
MEF2D (myocyte enhancer factor 2D)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(8):772-775.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MEF2DID43636ch1q22.html


External links

Nomenclature
HGNC (Hugo)MEF2D   6997
Cards
AtlasMEF2DID43636ch1q22
Entrez_Gene (NCBI)MEF2D  4209  myocyte enhancer factor 2D
Aliases
GeneCards (Weizmann)MEF2D
Ensembl hg19 (Hinxton)ENSG00000116604 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000116604 [Gene_View]  chr1:156463721-156490599 [Contig_View]  MEF2D [Vega]
ICGC DataPortalENSG00000116604
TCGA cBioPortalMEF2D
AceView (NCBI)MEF2D
Genatlas (Paris)MEF2D
WikiGenes4209
SOURCE (Princeton)MEF2D
Genetics Home Reference (NIH)MEF2D
Genomic and cartography
GoldenPath hg38 (UCSC)MEF2D  -     chr1:156463721-156490599 -  1q22   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MEF2D  -     1q22   [Description]    (hg19-Feb_2009)
EnsemblMEF2D - 1q22 [CytoView hg19]  MEF2D - 1q22 [CytoView hg38]
Mapping of homologs : NCBIMEF2D [Mapview hg19]  MEF2D [Mapview hg38]
OMIM600663   
Gene and transcription
Genbank (Entrez)AB210005 AF086193 AK027180 AK056972 AK308641
RefSeq transcript (Entrez)NM_001271629 NM_005920
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MEF2D
Cluster EST : UnigeneHs.744524 [ NCBI ]
CGAP (NCI)Hs.744524
Alternative Splicing GalleryENSG00000116604
Gene ExpressionMEF2D [ NCBI-GEO ]   MEF2D [ EBI - ARRAY_EXPRESS ]   MEF2D [ SEEK ]   MEF2D [ MEM ]
Gene Expression Viewer (FireBrowse)MEF2D [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4209
GTEX Portal (Tissue expression)MEF2D
Human Protein AtlasENSG00000116604-MEF2D [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14814   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ14814  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14814
Splice isoforms : SwissVarQ14814
PhosPhoSitePlusQ14814
Domaine pattern : Prosite (Expaxy)MADS_BOX_1 (PS00350)    MADS_BOX_2 (PS50066)   
Domains : Interpro (EBI)HJURP_C    MADS_MEF2-like    TF_MADSbox   
Domain families : Pfam (Sanger)HJURP_C (PF12347)    SRF-TF (PF00319)   
Domain families : Pfam (NCBI)pfam12347    pfam00319   
Domain families : Smart (EMBL)MADS (SM00432)  
Conserved Domain (NCBI)MEF2D
DMDM Disease mutations4209
Blocks (Seattle)MEF2D
SuperfamilyQ14814
Human Protein Atlas [tissue]ENSG00000116604-MEF2D [tissue]
Peptide AtlasQ14814
HPRD02810
IPIIPI00000784   IPI00216051   IPI00216052   IPI00216053   IPI00216054   IPI00394659   IPI01011776   IPI00982922   IPI00746421   
Protein Interaction databases
DIP (DOE-UCLA)Q14814
IntAct (EBI)Q14814
FunCoupENSG00000116604
BioGRIDMEF2D
STRING (EMBL)MEF2D
ZODIACMEF2D
Ontologies - Pathways
QuickGOQ14814
Ontology : AmiGOMAPK cascade  RNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II transcription factor activity, sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  osteoblast differentiation  endochondral ossification  chondrocyte differentiation  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  cytoplasm  transcription from RNA polymerase II promoter  apoptotic process  nervous system development  adult heart development  muscle organ development  activating transcription factor binding  skeletal muscle cell differentiation  protein homodimerization activity  histone deacetylase binding  intracellular membrane-bounded organelle  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  
Ontology : EGO-EBIMAPK cascade  RNA polymerase II regulatory region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II transcription factor activity, sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  osteoblast differentiation  endochondral ossification  chondrocyte differentiation  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  cytoplasm  transcription from RNA polymerase II promoter  apoptotic process  nervous system development  adult heart development  muscle organ development  activating transcription factor binding  skeletal muscle cell differentiation  protein homodimerization activity  histone deacetylase binding  intracellular membrane-bounded organelle  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  
Pathways : BIOCARTARole of MEF2D in T-cell Apoptosis [Genes]   
REACTOMEQ14814 [protein]
REACTOME PathwaysR-HSA-400253 [pathway]   
NDEx NetworkMEF2D
Atlas of Cancer Signalling NetworkMEF2D
Wikipedia pathwaysMEF2D
Orthology - Evolution
OrthoDB4209
GeneTree (enSembl)ENSG00000116604
Phylogenetic Trees/Animal Genes : TreeFamMEF2D
HOVERGENQ14814
HOGENOMQ14814
Homologs : HomoloGeneMEF2D
Homology/Alignments : Family Browser (UCSC)MEF2D
Gene fusions - Rearrangements
Fusion : MitelmanMEF2D/DAZAP1 [1q22/19p13.3]  
Fusion : MitelmanMEF2D/ZDHHC5 [1q22/11q12.1]  [t(1;11)(q22;q12)]  
Fusion: TCGA_MDACCMEF2D 1q22 ZDHHC5 11q12.1 GBM
Tumor Fusion PortalMEF2D
Fusion : TICdbMEF2D [1q22]  -  DAZAP1 [19p13.3]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMEF2D [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MEF2D
dbVarMEF2D
ClinVarMEF2D
1000_GenomesMEF2D 
Exome Variant ServerMEF2D
ExAC (Exome Aggregation Consortium)ENSG00000116604
GNOMAD BrowserENSG00000116604
Genetic variants : HAPMAP4209
Genomic Variants (DGV)MEF2D [DGVbeta]
DECIPHERMEF2D [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMEF2D 
Mutations
ICGC Data PortalMEF2D 
TCGA Data PortalMEF2D 
Broad Tumor PortalMEF2D
OASIS PortalMEF2D [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMEF2D  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMEF2D
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MEF2D
DgiDB (Drug Gene Interaction Database)MEF2D
DoCM (Curated mutations)MEF2D (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MEF2D (select a term)
intoGenMEF2D
NCG5 (London)MEF2D
Cancer3DMEF2D(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM600663   
Orphanet
DisGeNETMEF2D
MedgenMEF2D
Genetic Testing Registry MEF2D
NextProtQ14814 [Medical]
TSGene4209
GENETestsMEF2D
Target ValidationMEF2D
Huge Navigator MEF2D [HugePedia]
snp3D : Map Gene to Disease4209
BioCentury BCIQMEF2D
ClinGenMEF2D
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4209
Chemical/Pharm GKB GenePA30735
Clinical trialMEF2D
Miscellaneous
canSAR (ICR)MEF2D (select the gene name)
Probes
Litterature
PubMed79 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMEF2D
EVEXMEF2D
GoPubMedMEF2D
iHOPMEF2D
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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