MEF2D

Summary

MEF2D (myocyte enhancer factor 2D, HGNC:6997) is a protein-coding gene on chromosome 1q22, encoding Myocyte-specific enhancer factor 2D (Q14814). Transcriptional activator which binds specifically to the MEF2 element, 5’-YTAATTAR-3’, found in numerous muscle-specific, growth factor- and stress-induced genes.

This gene is a member of the myocyte-specific enhancer factor 2 (MEF2) family of transcription factors. Members of this family are involved in control of muscle and neuronal cell differentiation and development, and are regulated by class II histone deacetylases. Fusions of the encoded protein with Deleted in Azoospermia-Associated Protein 1 (DAZAP1) due to a translocation have been found in an acute lymphoblastic leukemia cell line, suggesting a role in leukemogenesis. The encoded protein may also be involved in Parkinson disease and myotonic dystrophy. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4209 — RefSeq curated summary.

At a glance

• GWAS associations: 30
• Clinical variants (ClinVar): 51 total
• Druggable target: yes
• Transcription factor: yes — 31 downstream targets (CollecTRI)
• MANE Select transcript: NM_005920

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6997
Approved symbol	MEF2D
Name	myocyte enhancer factor 2D
Location	1q22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000116604
Ensembl biotype	protein_coding
OMIM	600663
Entrez	4209

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 42 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000348159, ENST00000360595, ENST00000464356, ENST00000475587, ENST00000489057, ENST00000493077, ENST00000875425, ENST00000875426, ENST00000924773, ENST00000924774, ENST00000924775, ENST00000924776, ENST00000924777, ENST00000924778, ENST00000924779, ENST00000924780, ENST00000924781, ENST00000924782, ENST00000970792, ENST00000970793, ENST00000970794, ENST00000970796, ENST00000970798, ENST00000970800, ENST00000970801, ENST00000970802, ENST00000970804, ENST00000970805, ENST00000970807, ENST00000970809, ENST00000970810, ENST00000970812, ENST00000970813, ENST00000970814, ENST00000970815, ENST00000970816, ENST00000970817, ENST00000970818, ENST00000970819, ENST00000970820, ENST00000970821, ENST00000970822, ENST00000970823, ENST00000970824

RefSeq mRNA: 2 — MANE Select: NM_005920 NM_001271629, NM_005920

CCDS: CCDS1143, CCDS60304

Canonical transcript exons

ENST00000348159 — 12 exons

Exon	Start	End
ENSE00000788716	156479586	156479796
ENSE00000855928	156475108	156475237
ENSE00001054660	156476494	156476514
ENSE00001827180	156500486	156500775
ENSE00001918131	156463727	156467656
ENSE00003465878	156468780	156469020
ENSE00003470704	156477012	156477202
ENSE00003646187	156479290	156479346
ENSE00003705570	156480834	156480971
ENSE00003706575	156467993	156468299
ENSE00003710434	156483239	156483430
ENSE00003710866	156482437	156482640

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8898 / max 1107.3265, expressed in 1821 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15135	35.9234	1820
15134	7.6659	1372
15133	1.0786	410
15132	0.6937	396
15127	0.3072	120
15128	0.1371	63
15136	0.0461	11
15126	0.0379	12

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	97.79	gold quality
gastrocnemius	UBERON:0001388	97.44	gold quality
popliteal artery	UBERON:0002250	97.12	gold quality
tibial artery	UBERON:0007610	97.11	gold quality
muscle of leg	UBERON:0001383	96.69	gold quality
saphenous vein	UBERON:0007318	96.13	gold quality
aorta	UBERON:0000947	95.53	gold quality
apex of heart	UBERON:0002098	95.33	gold quality
sural nerve	UBERON:0015488	94.87	gold quality
muscle organ	UBERON:0001630	94.80	gold quality
mucosa of stomach	UBERON:0001199	94.59	gold quality
endocervix	UBERON:0000458	94.52	gold quality
right coronary artery	UBERON:0001625	94.45	gold quality
body of uterus	UBERON:0009853	94.40	gold quality
right atrium auricular region	UBERON:0006631	94.16	gold quality
heart left ventricle	UBERON:0002084	94.05	gold quality
endothelial cell	CL:0000115	93.93	gold quality
cardiac ventricle	UBERON:0002082	93.91	gold quality
left uterine tube	UBERON:0001303	93.62	gold quality
left coronary artery	UBERON:0001626	93.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.57	gold quality
ascending aorta	UBERON:0001496	93.53	gold quality
coronary artery	UBERON:0001621	93.53	gold quality
thoracic aorta	UBERON:0001515	93.49	gold quality
right ovary	UBERON:0002118	93.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.44	gold quality
left ovary	UBERON:0002119	93.43	gold quality
lower esophagus	UBERON:0013473	93.40	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.31	gold quality
cardiac atrium	UBERON:0002081	93.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.72
E-GEOD-75367	no	637.65
E-MTAB-6075	no	167.89

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

31 targets.

Target	Regulation
ADAM2
ATF3	Activation
ATM	Unknown
CD14	Activation
CD44
CDKN1A	Unknown
DAZAP1
DES	Activation
EIF3K
EP300	Activation
GADD45A
GADD45B
HDAC7	Unknown
IL10	Activation
JUN	Activation
KDM1A
MEF2A
MEF2D
MYF6	Activation
MYH1	Activation
MYH10	Activation
MYH13
MYH2	Activation
MYH7	Activation
MYOG
NR4A1	Repression
PPARGC1A	Activation
PRKACA
SLC2A4
SOST	Repression

Upstream regulators (CollecTRI, top): ESR2, HDAC7, JUN, MEF2A, MEF2D, NKX2-5

miRNA regulators (miRDB)

206 targeting MEF2D, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595

Literature-anchored findings (GeneRIF, showing 40)

• data implicate MEF2D in human cancer and suggest that MEF2D/DAZAP1 and/or DAZAP1/MEF2D contribute to leukemogenesis by altering signaling pathways normally regulated by wild-type MEF2D and DAZAP1 (PMID:15744350)
• A conserved pattern of alternative splicing in vertebrate MEF2 (myocyte enhancer factor 2) genes generates an acidic activation domain in MEF2 proteins selectively in tissues where MEF2 target genes are highly expressed. (MEF2) (PMID:15834131)
• histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications regulate MEF2 (PMID:16166628)
• These results reveal an unexpected role for HDAC3 and suggest a novel pathway through which MEF2 activity is controlled in vivo. (PMID:17158926)
• MEF2 proteins are an important component in Galpha13-mediated angiogenesis. (PMID:19093215)
• MEF2D levels were increased in the brains patients with Parkinson’s disease (PMID:19119233)
• ZAC1 is a novel and previously unknown regulator of cardiomyocyte Glut4 expression and glucose uptake; MEF2 is a regulator of ZAC1 expression in response to induction of hypertrophy (PMID:20363751)
• MEF2A and MEF2D play dual roles in human macrophages differentiation, as activators and as repressors of c-jun transcription. (PMID:20590529)
• direct regulation of complex I by mitochondrial MEF2D underlies its neuroprotective effects, and dysregulation of this pathway may contribute to Parkinson disease (PMID:21393861)
• The expression of MEF2D was higher in the higher clinical stage of nasopharyngeal carcinoma, but there was no correlation with survival rate. (PMID:22256741)
• Oxidation of survival factor MEF2D inhibits its function, underlies oxidative stress-induced neurotoxicity, and may be a part of the Parkinson disease pathogenic process. (PMID:24219011)
• The oncogenic properties of rhabdomyosarcoma cells can be partially attributed to the loss of MEF2D expression. (PMID:24279793)
• MEF2D-silencing abolished hepatocellular carcinoma tumorigenicity. (PMID:24390737)
• OA induced cell cycle arrest in lung cancer cells through miR-122/Cyclin G1/MEF2D pathway. This finding may contribute to the understanding of the molecular mechanism of OA’s anti-tumor activity (PMID:25472877)
• MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. (PMID:25733682)
• MEF2D suppression was shown to decrease the proliferation of osteosarcoma cells. (PMID:25814384)
• We found that in malignant glioma, there is an aberrantly high expression of MEF2D, which leads to poor prognosis of malignant glioma. The downregulation of MEF2D suppresses the proliferation of malignant glioma cell lines by inducing delay of S and G2/M phases of cell cycle and promoting apoptosis. (PMID:26234765)
• MEF2D overexpression participated in the growth of lung cancers and its aberrant expression may result from the reduction of tumor suppressor miR-218. (PMID:26409449)
• MEF2D regulates IGF-1-induced proliferation and apoptosis in CM development, indicating IGF-1-MEF2D pathway may be a useful target for treatment. (PMID:26563368)
• MEF2D is a direct target of miR-19. (PMID:26762410)
• Pokemon was found to enhance the migration and invasion of hepatocellular carcinoma by increasing MEF2D expression (PMID:26797719)
• MEF2d mRNA level is up-regulated in both sporadic and SOD1 + ALS patients. (PMID:26921792)
• These results suggest that PPARgamma may exert its antiproliferative effects by negatively regulating the MEF2D in CM cells, which through upregulation of miR-122, and PPARgamma/miR-122/MEF2D signaling pathway may be a novel target for treatment of CM. (PMID:27109478)
• MEF2D directly regulated transcription of the epithelial-mesenchymal transition driver gene ZEB1 and facilitated histone acetylation at the ZEB1 promoter in colorectal cancer cells (PMID:27364559)
• MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. (PMID:27507882)
• Our study suggests that the MEF2D, PRDM16 and ASTN2 genes from GWAS are associated with migraine susceptibility, especially migraine without aura , among Chinese patients. It appears that there is no association with serotonin receptor related genes. (PMID:28058730)
• MEF2D might be a potential biomarker during chronic inflammation-lung cancer transition, predicting the risk of lung cancer among patients with chronic respiratory diseases. (PMID:28340574)
• HIF-1alpha transactivates MEF2D expression by binding to the MEF2D gene promoter to induce angiogenesis in colorectal tumors. (PMID:28478181)
• In summary, we found that miR-1244 affected cisplatin-treated non-small cell lung cancer via MEF2D expression. (PMID:28498474)
• MEF2D variant associated with SLE affects MEF2D gene regulation and splicing. (PMID:30459414)
• Novel insights into the mechanisms underlying leukemia development by MEF2D fusion genes and the involvement of the deregulation of miRNA-mediated repression in cancer development. (PMID:30478446)
• Long non-coding RNA EPIC1 inhibits viability and invasion of osteosarcoma cells by promoting MEF2D ubiquitylation (PMID:30703420)
• MEF2D Disruption Promotes CD8+ T-Cell- Mediated Antitumor Immunity That Suppresses Hepatocellular Carcinoma Growth. MEF2D Attenuates Antitumor Immunity by Transactivating Programmed Cell Death 1 Ligand 1 Under Interferon Gamma Stimulation in Hepatocellular Carcinoma. (PMID:31678303)
• We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers. In these regions HDAC4 and HDAC9 can differentially influence H3K27 acetylation. (PMID:31754707)
• MEF2D-rearranged acute lymphoblastic leukemia resembles Burkitt lymphoma/leukemia. (PMID:31781846)
• Purification, crystallization, and X-ray diffraction analysis of myocyte enhancer factor 2D and DNA complex. (PMID:33221504)
• Nucleolar and spindleassociated protein 1 promotes nonsmall cell lung cancer progression and serves as an effector of myocyte enhancer factor 2D. (PMID:33650655)
• KDM1A Promotes Immunosuppression in Hepatocellular Carcinoma by Regulating PD-L1 through Demethylating MEF2D. (PMID:34307695)
• Coupling HDAC4 with transcriptional factor MEF2D abrogates SPRY4-mediated suppression of ERK activation and elicits hepatocellular carcinoma drug resistance. (PMID:34339801)
• Transcription factor MEF2D is required for the maintenance of MLL-rearranged acute myeloid leukemia. (PMID:34597364)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mef2d	ENSDARG00000040237
mus_musculus	Mef2d	ENSMUSG00000001419
rattus_norvegicus	Mef2d	ENSRNOG00000031778

Paralogs (4): MEF2A (ENSG00000068305), MEF2C (ENSG00000081189), SRF (ENSG00000112658), MEF2B (ENSG00000213999)

Protein

Protein identifiers

Myocyte-specific enhancer factor 2D — Q14814 (reviewed: Q14814)

All UniProt accessions (3): Q14814, A0A0G2JLL8, Q05BX2

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator which binds specifically to the MEF2 element, 5’-YTAATTAR-3’, found in numerous muscle-specific, growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. Plays a critical role in the regulation of neuronal apoptosis.

Subunit / interactions. Interacts with MYOG. Forms a complex with class II HDACs in undifferentiating cells. On myogenic differentiation, HDACs are released into the cytoplasm allowing MEF2s to interact with other proteins for activation. Interacts with HDAC4 (in undifferentiating cells); the interaction translocates MEF2D to nuclear dots. Forms a heterodimer with MEF2A. Interacts with MAPK7; the interaction phosphorylates but does not activate MEF2D. Interacts with CCAR2 and HDAC3.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated on Ser-444 by CDK5 is required for Lys-439 sumoylation and inhibits transcriptional activity. In neurons, enhanced CDK5 activity induced by neurotoxins promotes caspase 3-mediated cleavage leading to neuron apoptosis. Phosphorylation on Ser-180 can be enhanced by EGF. Phosphorylated and activated by CaMK4. Acetylated on Lys-439 by CREBBP. Acetylated by EP300. Deacetylated by SIRT1 and HDAC3. Sumoylated on Lys-439 with SUMO2 but not SUMO1; which inhibits transcriptional activity and myogenic activity. Desumoylated by SENP3. Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.

Domain organisation. The beta domain, missing in a number of isoforms, is required for enhancement of transcriptional activity.

Similarity. Belongs to the MEF2 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q14814-1	MEF2DAB	yes
Q14814-2	MEF2DA’B
Q14814-3	MEF2D0B
Q14814-4	MEF2DA0
Q14814-5	MEF2DA'0
Q14814-6	MEF2D00

RefSeq proteins (2): NP_001258558, NP_005911* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002100	TF_MADSbox	Domain
IPR022102	HJURP_C	Domain
IPR033896	MEF2-like_N	Domain
IPR036879	TF_MADSbox_sf	Homologous_superfamily

Pfam: PF00319, PF12347

UniProt features (45 total): mutagenesis site 12, modified residue 11, region of interest 5, splice variant 3, helix 3, strand 3, compositionally biased region 2, chain 1, domain 1, site 1, DNA-binding region 1, cross-link 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8C84	X-RAY DIFFRACTION	1.9
7X1N	X-RAY DIFFRACTION	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14814-F1	54.81	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 288–289 (cleavage)

Post-translational modifications (12): 98, 106, 110, 121, 180, 190, 231, 245, 251, 439, 444, 439

Mutagenesis-validated functional residues (12):

Position	Phenotype
180	abolishes mapk7- and egf-mediated transcriptional activation.
286	same transcriptional activity as for isoforms with beta domain.
287	abolishes transcriptional activity; when associated with n-288 and n-291.
288	abolishes cleavage by caspase 7.
288	abolishes transcriptional activity; when associated with q-287 and n-291.
289	same transcriptional activity as for isoforms with beta domain.
291	abolishes transcriptional activity; when associated with q-287 and n-288.
437	no effect on mapk7- or egf-mediated transcriptional activity.
438	abolishes k-439 sumoylation.
439	abolishes sumoylation and acetylation.
444	abolishes k-439 sumoylation. reduced neurotoxin-induced apoptosis of neuronal cells. more resistant to degradation.
444	no effect on k-439 sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-525793	Myogenesis
R-HSA-9031628	NGF-stimulated transcription
R-HSA-9707616	Heme signaling
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-1266738	Developmental Biology
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-2262752	Cellular responses to stress
R-HSA-400253
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 356 (showing top): GCACCTT_MIR18A_MIR18B, TAATAAT_MIR126, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, TATTATA_MIR374, PID_NFAT_3PATHWAY, TGACCTY_ERR1_Q2, GOBP_MUSCLE_CELL_PROLIFERATION, BROWNE_HCMV_INFECTION_12HR_UP, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, PATIL_LIVER_CANCER, RICKMAN_METASTASIS_DN, GOBP_POSITIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT

GO Biological Process (8): apoptotic process (GO:0006915), nervous system development (GO:0007399), adult heart development (GO:0007512), muscle organ development (GO:0007517), cell differentiation (GO:0030154), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), animal organ development (GO:0048513)

GO Molecular Function (11): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), histone deacetylase binding (GO:0042826), protein dimerization activity (GO:0046983), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Developmental Biology	1
Nuclear Events (kinase and transcription factor activation)	1
Cellular responses to stress	1
Circadian clock	1
Organelle biogenesis and maintenance	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signaling by NTRK1 (TRKA)	1
Cellular responses to stimuli	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
system development	1
heart development	1
animal organ development	1
muscle structure development	1
cellular developmental process	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
positive regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
anatomical structure development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of DNA-templated transcription	1
transcription regulator activity	1
enzyme binding	1
protein binding	1
DNA-binding transcription factor binding	1
transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

2585 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEF2D	HDAC9	Q9UKV0	874
MEF2D	ASH2L	Q9UBL3	872
MEF2D	MYOG	P15173	851
MEF2D	CABIN1	Q9Y6J0	846
MEF2D	EP300	Q09472	845
MEF2D	HDAC5	Q9UQL6	841
MEF2D	HDAC4	P56524	833
MEF2D	MYOD1	P15172	808
MEF2D	HDAC7	Q8WUI4	804
MEF2D	CRX	O43186	786
MEF2D	ZNF384	Q8TF68	754
MEF2D	DUX4L2	P0CJ85	718
MEF2D	HSPA8	P11142	713
MEF2D	NR4A1	P22736	679
MEF2D	SLC2A4RG	Q9NR83	651

IntAct

58 interactions, top by confidence:

A	B	Type	Score
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
WRAP53	TCP1	psi-mi:“MI:0914”(association)	0.690
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
Ywhaq	MEF2D	psi-mi:“MI:0915”(physical association)	0.590
MEF2D	Ywhaq	psi-mi:“MI:0407”(direct interaction)	0.590
MEF2D	Ywhaq	psi-mi:“MI:0915”(physical association)	0.590
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
MEF2D	Hdac5	psi-mi:“MI:0915”(physical association)	0.490
Hdac5	MEF2D	psi-mi:“MI:0915”(physical association)	0.490
MEF2D	CDK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MEF2D	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MEF2D	HDAC5	psi-mi:“MI:0915”(physical association)	0.370
HTT	MEF2D	psi-mi:“MI:0915”(physical association)	0.370
MEF2A	REV3L	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
BMI1	MEIS3P1	psi-mi:“MI:0914”(association)	0.350
MAPK14	PRKY	psi-mi:“MI:0914”(association)	0.350
MEF2A	PTPN5	psi-mi:“MI:0914”(association)	0.350
MEF2B	MEF2A	psi-mi:“MI:0914”(association)	0.350
HSPA8	SBNO1	psi-mi:“MI:0914”(association)	0.350
WRAP53	POTEF	psi-mi:“MI:0914”(association)	0.350
WRAP53	TMEM223	psi-mi:“MI:0914”(association)	0.350
MEF2D	YWHAQ	psi-mi:“MI:0914”(association)	0.350
AR	MED6	psi-mi:“MI:2364”(proximity)	0.270
RAVER1	KDM6A	psi-mi:“MI:2364”(proximity)	0.270
ERG	BCL9	psi-mi:“MI:2364”(proximity)	0.270
HNF1B	BCL9	psi-mi:“MI:2364”(proximity)	0.270
IRF4	ARID1A	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (128): MEF2D (Affinity Capture-RNA), MEF2D (Affinity Capture-RNA), MEF2D (Affinity Capture-RNA), MEF2D (Biochemical Activity), MEF2D (Affinity Capture-MS), MEF2D (Affinity Capture-Western), MEF2D (Reconstituted Complex), SKP2 (Reconstituted Complex), SKP2 (Affinity Capture-Western), MEF2D (Biochemical Activity), MEF2D (Co-fractionation), MEF2D (Affinity Capture-MS), MEF2D (Affinity Capture-MS), MEF2D (Affinity Capture-MS), MEF2D (Reconstituted Complex)

ESM2 similar proteins: A0A096MJY4, A0A486WWJ9, A2ICN5, A2VDZ3, A4UTP7, A8WL06, B7ZR65, H2LBU8, O89038, P10071, P40791, P55197, P55879, Q02078, Q03413, Q03414, Q06413, Q0VGT2, Q14814, Q2KIA0, Q2MJT0, Q32NP8, Q4VYR7, Q5IS56, Q5R444, Q5REW7, Q5U4X3, Q60929, Q61602, Q63943, Q6DFF5, Q6DIF3, Q6F2E7, Q7ZY13, Q8BUR3, Q8CFN5, Q91660, Q91661, Q9DE25, Q9EPK5

Diamond homologs: A0A096MJY4, A0A217EJJ0, A0A3Q7EKL1, A2IB53, A2ICN5, A2VDZ3, A4UTP7, A9YDN6, B0XYE0, B4YPV4, B4YPW6, D7KQR8, D7KWY6, D7SMN6, F6I457, G4MWZ7, I1GN76, O22328, O55087, O65874, O89038, P0C5B0, P0C5B1, P0DI14, P29381, P29385, P29386, P35631, P38128, P40791, Q02078, Q02080, Q03413, Q03414, Q03489, Q06413, Q0J466, Q10CQ1, Q12224, Q14814

SIGNOR signaling

28 interactions.

A	Effect	B	Mechanism
YWHAQ	up-regulates	MEF2D	binding
NFATC2	up-regulates	MEF2D	binding
CABIN1	down-regulates	MEF2D
MEF2D	“form complex”	“Myog/SWI/SNF complex”	binding
MAPK14	“up-regulates activity”	MEF2D	phosphorylation
MEF2D	up-regulates	ASH2L
CDK4	down-regulates	MEF2D	binding
CyclinD/CDK4	down-regulates	MEF2D	binding
EP300	up-regulates	MEF2D	binding
MAPK7	up-regulates	MEF2D	phosphorylation
AKT	up-regulates	MEF2D
DYRK1A	“down-regulates activity”	MEF2D	phosphorylation
CDK5	“down-regulates activity”	MEF2D	phosphorylation
HDAC4	down-regulates	MEF2D	binding
AKT1	up-regulates	MEF2D
HDAC5	down-regulates	MEF2D	binding
TGFB1	down-regulates	MEF2D
MEF2D	“up-regulates quantity by expression”	MYH2	“transcriptional regulation”
MEF2D	“up-regulates quantity by expression”	MYF6	“transcriptional regulation”
MEF2D	“up-regulates quantity by expression”	MYH1	“transcriptional regulation”
MEF2D	“up-regulates quantity by expression”	MYH10	“transcriptional regulation”
MEF2D	“up-regulates quantity by expression”	DES	“transcriptional regulation”
MEF2D	“up-regulates quantity by expression”	MYH7	“transcriptional regulation”
CyclinD/CDK4	“down-regulates quantity by destabilization”	MEF2D	phosphorylation
SCF-SKP2	“down-regulates quantity by destabilization”	MEF2D	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MITF-M-regulated melanocyte development	6	13.4×	4e-04
Signaling by Interleukins	6	7.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
neuron differentiation	6	9.6×	2e-03
chromatin remodeling	7	8.1×	2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

51 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2290 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156475238:C:CC	acceptor_gain	1.0000
1:156479793:TTGA:T	acceptor_gain	1.0000
1:156479794:TGA:T	acceptor_gain	1.0000
1:156479797:C:CC	acceptor_gain	1.0000
1:156480828:GCTCA:G	donor_loss	1.0000
1:156480829:CTCA:C	donor_loss	1.0000
1:156480830:TCA:T	donor_loss	1.0000
1:156480831:CACCC:C	donor_loss	1.0000
1:156480832:A:AC	donor_gain	1.0000
1:156480832:AC:A	donor_gain	1.0000
1:156480832:ACC:A	donor_gain	1.0000
1:156480832:ACCC:A	donor_gain	1.0000
1:156480833:C:CC	donor_gain	1.0000
1:156480833:C:T	donor_loss	1.0000
1:156480833:CC:C	donor_gain	1.0000
1:156480833:CCC:C	donor_gain	1.0000
1:156480833:CCCC:C	donor_gain	1.0000
1:156480967:AGGGT:A	acceptor_gain	1.0000
1:156480968:GGGT:G	acceptor_gain	1.0000
1:156480969:GGT:G	acceptor_gain	1.0000
1:156480970:GTCT:G	acceptor_loss	1.0000
1:156480971:TCTG:T	acceptor_loss	1.0000
1:156480972:C:CA	acceptor_loss	1.0000
1:156480972:C:CC	acceptor_gain	1.0000
1:156482432:CCCA:C	donor_loss	1.0000
1:156482433:CCACC:C	donor_loss	1.0000
1:156482434:CACCT:C	donor_loss	1.0000
1:156482435:AC:A	donor_loss	1.0000
1:156482436:CC:C	donor_loss	1.0000
1:156482636:GTCAC:G	acceptor_gain	1.0000

AlphaMissense

3365 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156480967:A:G	L88P	1.000
1:156482444:A:C	I84S	1.000
1:156482444:A:G	I84T	1.000
1:156482444:A:T	I84N	1.000
1:156482452:G:C	N81K	1.000
1:156482452:G:T	N81K	1.000
1:156482453:T:A	N81I	1.000
1:156482456:G:A	T80I	1.000
1:156482461:G:C	S78R	1.000
1:156482461:G:T	S78R	1.000
1:156482463:T:G	S78R	1.000
1:156482481:A:C	Y72D	1.000
1:156482481:A:G	Y72H	1.000
1:156482486:G:T	T70K	1.000
1:156482489:T:C	Y69C	1.000
1:156482489:T:G	Y69S	1.000
1:156482490:A:C	Y69D	1.000
1:156482490:A:G	Y69H	1.000
1:156482490:A:T	Y69N	1.000
1:156482491:C:A	K68N	1.000
1:156482491:C:G	K68N	1.000
1:156482493:T:C	K68E	1.000
1:156482495:A:C	L67R	1.000
1:156482495:A:G	L67P	1.000
1:156482495:A:T	L67H	1.000
1:156482496:G:A	L67F	1.000
1:156482498:A:C	L66R	1.000
1:156482498:A:G	L66P	1.000
1:156482498:A:T	L66Q	1.000
1:156482501:A:G	V65A	1.000

dbSNP variants (sampled 300 via entrez): RS1000041983 (1:156496296 C>T), RS1000096003 (1:156490607 C>T), RS1000127455 (1:156490919 G>A), RS1000185490 (1:156472938 CTGA>C), RS1000256139 (1:156466681 G>A), RS1000258277 (1:156490796 T>C), RS1000301620 (1:156484819 T>A,G), RS1000307666 (1:156472411 C>T), RS1000539968 (1:156500422 C>G,T), RS1000712854 (1:156466102 C>T), RS1000731032 (1:156489600 C>T), RS1000816628 (1:156478912 G>C), RS1000861765 (1:156489735 A>G), RS1000873146 (1:156482973 T>C), RS1000928367 (1:156500830 G>A,T)

Disease associations

OMIM: gene MIM:600663 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST001563_1	Migraine	7.000000e-11
GCST002079_28	Migraine - clinic-based	1.000000e-07
GCST002081_19	Migraine	1.000000e-08
GCST003720_26	Migraine	9.000000e-22
GCST003986_5	Migraine	2.000000e-18
GCST004603_169	Platelet count	4.000000e-11
GCST004607_205	Plateletcrit	2.000000e-14
GCST005337_8	Headache	2.000000e-11
GCST007939_11	Medication use (antimigraine preparations)	2.000000e-09
GCST010346_31	TPE interval (resting)	9.000000e-30
GCST010346_48	TPE interval (resting)	3.000000e-12
GCST010346_5	TPE interval (resting)	3.000000e-21
GCST010796_4804	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_4805	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10
GCST010796_4806	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-14
GCST010796_4807	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-16
GCST010796_4808	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-17
GCST010796_4819	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-12
GCST010796_4820	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-16
GCST012226_581	Waist circumference adjusted for body mass index	3.000000e-09
GCST012231_156	A body shape index	4.000000e-08
GCST90002393_157	Monocyte count	4.000000e-13
GCST90002400_524	Plateletcrit	2.000000e-39
GCST90002402_495	Platelet count	1.000000e-25
GCST90002407_2	White blood cell count	4.000000e-09
GCST90020024_609	A body shape index	3.000000e-10
GCST90020025_1225	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST90020027_1810	Waist-hip index	4.000000e-09
GCST90020029_1230	Waist circumference adjusted for body mass index	8.000000e-12
GCST90020029_1232	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0009939	Antimigraine preparation use measurement
EFO:0004644	TPE interval measurement
EFO:0004327	electrocardiography
EFO:0007789	BMI-adjusted waist circumference
EFO:0005091	monocyte count
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL6066549 (PROTEIN COMPLEX), CHEMBL6066585 (PROTEIN COMPLEX)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1050316	MEF2D		0.00	0

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[6-(2-aminoanilino)-6-oxohexyl]-4-bromobenzamide	IC50	70 nM	US-9133105: Transcription factor modulators
N’-(2-aminophenyl)-N-(3-hydroxyphenyl)heptanediamide	IC50	90 nM	US-9133105: Transcription factor modulators
N’-(2-aminophenyl)-N-(4-hydroxyphenyl)heptanediamide	IC50	100 nM	US-9133105: Transcription factor modulators
N-(2-aminophenyl)-N’-(5-bromo-3-pyridinyl)heptanediamide	IC50	110 nM	US-9133105: Transcription factor modulators

ChEMBL bioactivities

137 potent at pChembl≥5 of 140 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	IC50	70	nM	CHEMBL6045867
7.15	IC50	71	nM	CHEMBL5844064
6.85	IC50	140	nM	CHEMBL5952651
6.85	IC50	140	nM	CHEMBL5983410
6.68	IC50	210	nM	CHEMBL5923127
6.60	IC50	250	nM	CHEMBL5814575
6.58	IC50	260	nM	CHEMBL5864417
6.58	IC50	260	nM	CHEMBL5951886
6.58	IC50	260	nM	CHEMBL5894077
6.57	IC50	270	nM	CHEMBL5860411
6.57	IC50	270	nM	CHEMBL5851469
6.57	IC50	270	nM	CHEMBL5871944
6.57	IC50	270	nM	CHEMBL6060595
6.55	IC50	280	nM	CHEMBL5937528
6.51	IC50	310	nM	CHEMBL5976479
6.50	IC50	320	nM	CHEMBL5873395
6.50	IC50	320	nM	CHEMBL5809404
6.50	IC50	320	nM	CHEMBL5806040
6.50	IC50	320	nM	CHEMBL5993076
6.46	IC50	350	nM	CHEMBL6059964
6.46	IC50	350	nM	CHEMBL6044994
6.46	IC50	350	nM	CHEMBL5874735
6.46	IC50	350	nM	CHEMBL6002113
6.43	IC50	370	nM	CHEMBL5931554
6.42	IC50	380	nM	CHEMBL5930419
6.42	IC50	380	nM	CHEMBL6021867
6.42	IC50	380	nM	CHEMBL5987830
6.42	IC50	380	nM	CHEMBL5853678
6.41	IC50	390	nM	CHEMBL5983410
6.40	IC50	400	nM	CHEMBL5785543
6.39	IC50	410	nM	CHEMBL5971476
6.38	IC50	420	nM	CHEMBL5752996
6.38	IC50	420	nM	CHEMBL5765745
6.36	IC50	440	nM	CHEMBL5749055
6.36	IC50	440	nM	CHEMBL5921254
6.35	IC50	450	nM	CHEMBL5884092
6.34	IC50	460	nM	CHEMBL5815445
6.33	IC50	470	nM	CHEMBL5843810
6.33	IC50	470	nM	CHEMBL5853678
6.33	IC50	470	nM	CHEMBL5752146
6.31	IC50	490	nM	CHEMBL5794256
6.30	IC50	500	nM	CHEMBL6033618
6.29	IC50	510	nM	CHEMBL5871944
6.29	IC50	510	nM	CHEMBL5841216
6.27	IC50	540	nM	CHEMBL5986569
6.27	IC50	540	nM	CHEMBL5840536
6.25	IC50	560	nM	CHEMBL5966331
6.25	IC50	560	nM	CHEMBL5911274
6.25	IC50	560	nM	CHEMBL6034228
6.24	IC50	570	nM	CHEMBL6060595

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
bisphenol A	decreases methylation, increases expression	2
arsenite	affects binding, decreases reaction, increases methylation	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Cisplatin	decreases expression	2
Tretinoin	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
didecyldimethylammonium	increases expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
pinostrobin	increases expression	1
abrine	increases expression	1
palbociclib	affects binding, decreases reaction, increases phosphorylation	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
bis(3)-cognitin	increases response to substance	1
Temozolomide	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5737778	Binding	Inhibitory Effects of the Compounds on MEF2D and P300 Protein Interactions: Detection of MEF2D and P300 interactions. The same system that was used in Example 19 is used in here to detect MEF2D and P300 interactions. In this assay, two sepa	Myocyte enhancer factor 2 (MEF2) modulators

Cellosaurus cell lines

10 cell lines: 10 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1374	LC4-1	Cancer cell line	Female
CVCL_1631	P30/OHK	Cancer cell line	Female
CVCL_8486	Kasumi-7	Cancer cell line	Female
CVCL_8488	Kasumi-9	Cancer cell line	Male
CVCL_A083	YCUB-4	Cancer cell line	Male
CVCL_A084	YCUB-4R	Cancer cell line	Male
CVCL_A323	TS-2	Cancer cell line	Female
CVCL_D3ZJ	KCB9	Cancer cell line	Female
CVCL_D4AF	M4A1-M2B9	Cancer cell line	Male
CVCL_GZ89	K562 eGFP-MEF2D	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.