MDFI

Summary

MDFI (MyoD family inhibitor, HGNC:6967) is a protein-coding gene on chromosome 6p21.1, encoding MyoD family inhibitor (Q99750). Inhibits the transactivation activity of the Myod family of myogenic factors and represses myogenesis.

This protein is a transcription factor that negatively regulates other myogenic family proteins. Studies of the mouse homolog, I-mf, show that it interferes with myogenic factor function by masking nuclear localization signals and preventing DNA binding. Knockout mouse studies show defects in the formation of vertebrae and ribs that also involve cartilage formation in these structures.

Source: NCBI Gene 4188 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_005586

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6967
Approved symbol	MDFI
Name	MyoD family inhibitor
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	I-mfa
Ensembl gene	ENSG00000112559
Ensembl biotype	protein_coding
OMIM	604971
Entrez	4188

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 retained_intron

ENST00000230321, ENST00000373050, ENST00000373051, ENST00000419164, ENST00000432027, ENST00000435476, ENST00000441667, ENST00000446650, ENST00000471092, ENST00000909784, ENST00000909785, ENST00000928623, ENST00000928624, ENST00000928625, ENST00000928626, ENST00000928627

RefSeq mRNA: 4 — MANE Select: NM_005586 NM_001300804, NM_001300805, NM_001300806, NM_005586

CCDS: CCDS4857, CCDS75451

Canonical transcript exons

ENST00000230321 — 5 exons

Exon	Start	End
ENSE00000750679	41646126	41646308
ENSE00000750680	41649619	41649843
ENSE00000849911	41638739	41638825
ENSE00001459410	41638468	41638652
ENSE00001612667	41653319	41654244

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 93.47.

FANTOM5 (CAGE): breadth broad, TPM avg 15.1987 / max 328.6915, expressed in 842 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67765	5.8742	575
67762	5.2687	562
67764	3.1866	563
67766	0.3802	234
67761	0.2943	164
67768	0.0930	60
67763	0.0642	20
67767	0.0374	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	93.47	gold quality
lower esophagus mucosa	UBERON:0035834	91.75	gold quality
ventricular zone	UBERON:0003053	91.64	gold quality
esophagus mucosa	UBERON:0002469	89.34	gold quality
embryo	UBERON:0000922	87.68	gold quality
omental fat pad	UBERON:0010414	87.34	gold quality
peritoneum	UBERON:0002358	87.32	gold quality
parotid gland	UBERON:0001831	86.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.60	gold quality
vena cava	UBERON:0004087	86.37	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.30	gold quality
pharyngeal mucosa	UBERON:0000355	86.14	gold quality
ectocervix	UBERON:0012249	85.66	gold quality
minor salivary gland	UBERON:0001830	85.62	gold quality
saliva-secreting gland	UBERON:0001044	84.55	gold quality
body of tongue	UBERON:0011876	84.32	silver quality
mouth mucosa	UBERON:0003729	84.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.22	gold quality
tongue squamous epithelium	UBERON:0006919	83.80	gold quality
gall bladder	UBERON:0002110	83.76	gold quality
endocervix	UBERON:0000458	83.42	gold quality
vagina	UBERON:0000996	83.28	gold quality
right ovary	UBERON:0002118	83.16	gold quality
gluteal muscle	UBERON:0002000	83.13	gold quality
tongue	UBERON:0001723	82.63	silver quality
upper lobe of left lung	UBERON:0008952	82.37	gold quality
subthalamic nucleus	UBERON:0001906	81.71	gold quality
left ovary	UBERON:0002119	81.34	gold quality
inferior vagus X ganglion	UBERON:0005363	81.26	silver quality
cardia of stomach	UBERON:0001162	81.15	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8221	yes	480.59
E-MTAB-6701	yes	114.69
E-HCAD-10	yes	63.00
E-CURD-112	yes	15.91
E-ANND-3	yes	8.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting MDFI, 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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-4483	98.09	64.12	1642

Literature-anchored findings (GeneRIF, showing 7)

• I-mfa functions as a molecular switch to suppress the store dependence of TRPC1 (PMID:14530267)
• These results suggest that the physical and functional interaction between Zic and I-mfa proteins can play a role in the vertebrate development. (PMID:15207726)
• I-mfa domain proteins may be involved in their oncogenic functions by negatively regulating their transcriptional activities. (PMID:21664411)
• MDFI was significantly hypermethylated in colorectal cancer tissues when compared with adjacent normal colorectal tissues. (PMID:28782576)
• Opposite Roles of the JMJD1A Interaction Partners MDFI and MDFIC in Colorectal Cancer. (PMID:32457453)
• Multifaceted array-based keloidal gene expression profiling reveals specific MDFI upregulation in keloid lesions. (PMID:33899950)
• MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway. (PMID:38375821)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mdfi	ENSDARG00000089564
mus_musculus	Mdfi	ENSMUSG00000032717
rattus_norvegicus	Mdfi	ENSRNOG00000014987

Paralogs (2): MDFIC (ENSG00000135272), MDFIC2 (ENSG00000242120)

Protein

Protein identifiers

MyoD family inhibitor — Q99750 (reviewed: Q99750)

Alternative names: Myogenic repressor I-mf

All UniProt accessions (7): B1AKB6, B1AKB7, B1AKB8, B1AKB9, B1AKC0, B1AKC1, Q99750

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits the transactivation activity of the Myod family of myogenic factors and represses myogenesis. Acts by associating with Myod family members and retaining them in the cytoplasm by masking their nuclear localization signals. Can also interfere with the DNA-binding activity of Myod family members. Plays an important role in trophoblast and chondrogenic differentiation. Regulates the transcriptional activity of TCF7L1/TCF3 by interacting directly with TCF7L1/TCF3 and preventing it from binding DNA. Binds to the axin complex, resulting in an increase in the level of free beta-catenin. Affects axin regulation of the WNT and JNK signaling pathways. Regulates the activity of mechanosensitive Piezo channel.

Subunit / interactions. Interacts (via C-terminus) with AXIN1 and LEF1. Interacts with CCNT2. Interacts (via C-terminus) with Piezo channel composed of PIEZO1 or PIEZO2; the interaction prolongs Piezo channel inactivation.

Subcellular location. Nucleus. Cytoplasm.

Similarity. Belongs to the MDFI family.

RefSeq proteins (4): NP_001287733, NP_001287734, NP_001287735, NP_005577* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026134	MDFI/MDFIC	Family

Pfam: PF15316

UniProt features (5 total): region of interest 2, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99750-F1	51.18	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 143 (showing top): AP1_01, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_AXIS_SPECIFICATION, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_EMBRYONIC_PLACENTA_DEVELOPMENT, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), dorsal/ventral axis specification (GO:0009950), regulation of Wnt signaling pathway (GO:0030111), negative regulation of Wnt signaling pathway (GO:0030178), maintenance of protein location in cell (GO:0032507), negative regulation of DNA-templated transcription (GO:0045892), regulation of JNK cascade (GO:0046328), embryonic skeletal system morphogenesis (GO:0048704), trophoblast giant cell differentiation (GO:0060707), regulation of gene expression (GO:0010468), cell differentiation (GO:0030154)

GO Molecular Function (4): identical protein binding (GO:0042802), protein sequestering activity (GO:0140311), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
axis specification	1
dorsal/ventral pattern formation	1
regulation of signal transduction	1
negative regulation of signal transduction	1
regulation of Wnt signaling pathway	1
maintenance of protein location	1
maintenance of location in cell	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
JNK cascade	1
regulation of MAPK cascade	1
embryonic organ morphogenesis	1
skeletal system morphogenesis	1
embryonic skeletal system development	1
cell differentiation involved in embryonic placenta development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cellular developmental process	1
molecular sequestering activity	1
regulation of gene expression	1
transcription regulator activity	1
molecular function inhibitor activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MDFI	MYOD1	P15172	853
MDFI	ZIC3	O60481	508
MDFI	HOMER2	Q9NSB8	494
MDFI	HOMER3	Q9NSC5	494
MDFI	HOMER1	Q86YM7	481
MDFI	CALM1	P02593	476
MDFI	CALML3	P27482	473
MDFI	CALML6	Q8TD86	473
MDFI	CALML4	Q96GE6	473
MDFI	CALML5	Q9NZT1	473
MDFI	FKBP3	Q00688	467
MDFI	CAV1	Q03135	457
MDFI	MEOX2	P50222	433
MDFI	MX1	P20591	431
MDFI	FGFR1	P11362	421

IntAct

1564 interactions, top by confidence:

A	B	Type	Score
PRKAB2	MDFI	psi-mi:“MI:0915”(physical association)	0.880
MDFI	ZNF136	psi-mi:“MI:0915”(physical association)	0.880
MDFI	ZNF440	psi-mi:“MI:0915”(physical association)	0.880
ZBTB24	MDFI	psi-mi:“MI:0915”(physical association)	0.840
MDFI	ZBTB24	psi-mi:“MI:0915”(physical association)	0.840
ZNF439	MDFI	psi-mi:“MI:0915”(physical association)	0.830
MDFI	ZNF559	psi-mi:“MI:0915”(physical association)	0.830
ENKD1	MDFI	psi-mi:“MI:0915”(physical association)	0.830
ZNF581	MDFI	psi-mi:“MI:0915”(physical association)	0.830
C10orf62	MDFI	psi-mi:“MI:0915”(physical association)	0.820
MDFI	SLC25A10	psi-mi:“MI:0915”(physical association)	0.820
MDFI	C10orf62	psi-mi:“MI:0915”(physical association)	0.820
MDFI	NPDC1	psi-mi:“MI:0915”(physical association)	0.800
MDFI	CREB5	psi-mi:“MI:0915”(physical association)	0.790
TUSC2	MDFI	psi-mi:“MI:0915”(physical association)	0.780
WNT11	MDFI	psi-mi:“MI:0915”(physical association)	0.780
MDFI	HTR1B	psi-mi:“MI:0915”(physical association)	0.780
MDFI	PIN1	psi-mi:“MI:0915”(physical association)	0.780
AVPI1	MDFI	psi-mi:“MI:0915”(physical association)	0.780
CCDC116	MDFI	psi-mi:“MI:0915”(physical association)	0.780
ZNF417	MDFI	psi-mi:“MI:0915”(physical association)	0.780
MDFI	BAHD1	psi-mi:“MI:0915”(physical association)	0.780
DCANP1	MDFI	psi-mi:“MI:0915”(physical association)	0.780
PTPMT1	MDFI	psi-mi:“MI:0915”(physical association)	0.780
HEYL	MDFI	psi-mi:“MI:0915”(physical association)	0.780
ZNF223	MDFI	psi-mi:“MI:0915”(physical association)	0.780
MDFI	ZNF490	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (652): MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), MDFI (Two-hybrid), NAB2 (Two-hybrid), REG3A (Two-hybrid), PIN1 (Two-hybrid)

ESM2 similar proteins: A0PJX4, A2A8U2, A4D2P6, A6QM06, D4A6L0, E1BBQ2, O15079, O60320, P12755, P49797, P97260, Q0D2I5, Q12770, Q15884, Q1RMB5, Q3TS39, Q3UPR0, Q4FZH1, Q5MNU5, Q5SNT2, Q5T848, Q5XKK7, Q60698, Q6A044, Q7T0Z7, Q7TMB0, Q7TPB0, Q810F0, Q86XR5, Q8BX43, Q8BXL9, Q8C419, Q8CA71, Q8K064, Q8K2Y3, Q8N114, Q8NDY8, Q8WV15, Q91WM6, Q92537

Diamond homologs: P70331, Q99750, A0A1B0GVS7, Q8BX65, Q98SK0, Q9P1T7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MDFI	“down-regulates activity”	MYF5	binding
MDFI	“down-regulates activity”	MYOD1	binding
MDFI	“down-regulates activity”	MYOG	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1062 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41637269:TAGCC:T	donor_gain	1.0000
6:41637270:AGCC:A	donor_gain	1.0000
6:41637270:AGCCG:A	donor_loss	1.0000
6:41637271:GCC:G	donor_gain	1.0000
6:41637271:GCCG:G	donor_gain	1.0000
6:41637271:GCCGT:G	donor_loss	1.0000
6:41637272:CC:C	donor_gain	1.0000
6:41637272:CCGT:C	donor_loss	1.0000
6:41637273:CGTA:C	donor_loss	1.0000
6:41637274:G:GG	donor_gain	1.0000
6:41637274:GTA:G	donor_loss	1.0000
6:41637275:T:A	donor_loss	1.0000
6:41638210:G:GT	donor_gain	1.0000
6:41638250:G:GT	donor_gain	1.0000
6:41653317:A:AG	acceptor_gain	1.0000
6:41653318:G:GG	acceptor_gain	1.0000
6:41637276:AAGTA:A	donor_loss	0.9900
6:41646124:A:AG	acceptor_gain	0.9900
6:41646125:G:GG	acceptor_gain	0.9900
6:41646309:G:GG	donor_gain	0.9900
6:41649617:AGGC:A	acceptor_gain	0.9900
6:41653304:ACC:A	acceptor_gain	0.9900
6:41653306:C:A	acceptor_gain	0.9900
6:41653310:A:AG	acceptor_gain	0.9900
6:41653311:C:G	acceptor_gain	0.9900
6:41653315:GCAGA:G	acceptor_loss	0.9900
6:41653316:CA:C	acceptor_loss	0.9900
6:41653317:AGA:A	acceptor_loss	0.9900
6:41653317:AGACT:A	acceptor_gain	0.9900
6:41653318:G:C	acceptor_loss	0.9900

AlphaMissense

1594 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41653564:T:C	F244L	0.995
6:41653566:C:A	F244L	0.995
6:41653566:C:G	F244L	0.995
6:41653351:T:C	F173L	0.994
6:41653353:C:A	F173L	0.994
6:41653353:C:G	F173L	0.994
6:41653345:T:C	C171R	0.993
6:41653535:A:T	E234V	0.992
6:41653538:T:C	I235T	0.992
6:41653542:C:G	C236W	0.991
6:41653355:G:A	C174Y	0.990
6:41653528:T:C	C232R	0.990
6:41653540:T:C	C236R	0.990
6:41653349:T:C	L172P	0.989
6:41653372:T:C	C180R	0.989
6:41653538:T:G	I235S	0.989
6:41653549:T:C	C239R	0.989
6:41653561:T:C	C243R	0.989
6:41653354:T:C	C174R	0.988
6:41653532:T:C	L233P	0.988
6:41653541:G:A	C236Y	0.988
6:41653565:T:G	F244C	0.988
6:41653546:G:A	E238K	0.986
6:41653352:T:G	F173C	0.985
6:41653360:T:C	F176L	0.985
6:41653362:C:A	F176L	0.985
6:41653362:C:G	F176L	0.985
6:41653340:T:C	L169P	0.984
6:41653346:G:A	C171Y	0.984
6:41653347:C:G	C171W	0.984

dbSNP variants (sampled 300 via entrez): RS1000018861 (6:41644371 A>G), RS1000188710 (6:41646051 G>C,T), RS1000312571 (6:41650972 G>A,T), RS1000549768 (6:41640345 C>G), RS1000571033 (6:41647297 C>T), RS1000636912 (6:41641570 T>C,G), RS1000645351 (6:41652353 A>G), RS1000649943 (6:41645819 T>C), RS1000655246 (6:41652548 C>G,T), RS1000700392 (6:41639057 C>A,T), RS1000776076 (6:41651301 T>C), RS1001133055 (6:41636154 G>A), RS1001254705 (6:41652080 G>A), RS1001521535 (6:41640875 T>C), RS1001522197 (6:41635766 C>T)

Disease associations

OMIM: gene MIM:604971 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008531_3	Grapefruit juice consumption	9.000000e-07
GCST009277_7	Subjective response to placebo treatment in childhood asthma (change in cough/wheeze)	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010094	grapefruit juice consumption measurement
EFO:0008344	response to placebo
EFO:0010068	respiratory symptom change measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
Nickel	increases expression	2
Valproic Acid	decreases expression, increases methylation, affects expression	2
bisphenol A	decreases expression	1
kojic acid	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
cupric chloride	increases expression	1
nickel sulfate	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
bazedoxifene	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
licochalcone B	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arbutin	decreases expression	1
Dexamethasone	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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