TCF15

Summary

TCF15 (transcription factor 15, HGNC:11627) is a protein-coding gene on chromosome 20p13, encoding Transcription factor 15 (Q12870). Early transcription factor that plays a key role in somitogenesis, paraxial mesoderm development and regulation of stem cell pluripotency.

The protein encoded by this gene is found in the nucleus and may be involved in the early transcriptional regulation of patterning of the mesoderm. The encoded basic helix-loop-helix protein requires dimerization with another basic helix-loop-helix protein for efficient DNA binding.

Source: NCBI Gene 6939 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 40 total — 1 pathogenic
• MANE Select transcript: NM_004609

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11627
Approved symbol	TCF15
Name	transcription factor 15
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	EC2, PARAXIS, bHLHa40
Ensembl gene	ENSG00000125878
Ensembl biotype	protein_coding
OMIM	601010
Entrez	6939

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000246080

RefSeq mRNA: 1 — MANE Select: NM_004609 NM_004609

CCDS: CCDS33432

Canonical transcript exons

ENST00000246080 — 2 exons

Exon	Start	End
ENSE00000858551	604257	604665
ENSE00000858552	609713	610309

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 92.02.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6121 / max 25.0981, expressed in 272 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185977	0.6121	272

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	92.02	gold quality
heart right ventricle	UBERON:0002080	91.66	silver quality
apex of heart	UBERON:0002098	91.05	gold quality
vena cava	UBERON:0004087	90.10	gold quality
gluteal muscle	UBERON:0002000	89.54	silver quality
tongue squamous epithelium	UBERON:0006919	89.28	gold quality
triceps brachii	UBERON:0001509	88.65	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.78	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	87.65	silver quality
olfactory bulb	UBERON:0002264	86.78	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.15	silver quality
body of tongue	UBERON:0011876	86.04	silver quality
diaphragm	UBERON:0001103	85.64	gold quality
biceps brachii	UBERON:0001507	84.86	silver quality
cardiac ventricle	UBERON:0002082	84.47	gold quality
heart left ventricle	UBERON:0002084	84.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.22	gold quality
orbitofrontal cortex	UBERON:0004167	83.78	gold quality
pericardium	UBERON:0002407	83.33	silver quality
myocardium	UBERON:0002349	82.24	silver quality
pharyngeal mucosa	UBERON:0000355	81.97	silver quality
tongue	UBERON:0001723	81.83	silver quality
skeletal muscle tissue	UBERON:0001134	81.79	gold quality
pons	UBERON:0000988	81.70	silver quality
nasal cavity epithelium	UBERON:0005384	81.37	gold quality
medial globus pallidus	UBERON:0002477	80.63	silver quality
globus pallidus	UBERON:0001875	80.25	silver quality
left ventricle myocardium	UBERON:0006566	79.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	79.27	silver quality
cervix squamous epithelium	UBERON:0006922	78.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
MKX	Unknown
NKX3-1	Unknown
NKX3-2	Unknown
PAX3	Unknown
SCX	Activation
TKT
TNMD

Upstream regulators (CollecTRI, top): SNAI2

miRNA regulators (miRDB)

21 targeting TCF15, 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-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-4312	99.34	67.30	511
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-1972	97.67	67.38	1172
HSA-MIR-301A-5P	96.88	68.07	931
HSA-MIR-301B-5P	96.88	67.75	946
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-4256	96.22	67.70	669
HSA-MIR-11181-5P	96.12	67.46	665
HSA-MIR-4449	88.89	64.59	48
HSA-MIR-6789-3P	83.91	59.77	58

Literature-anchored findings (GeneRIF, showing 3)

• Activation of TGFbeta recruits p300 to the KLF5-Smad complex to acetylate KLF5, and the complex with acetylated KLF5 binds to the Smad binding element and alters the binding of other factors to p15 promoter to induce its transcription (PMID:19419955)
• Microarray profiling on freshly isolated ECs had a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was similar in skeletal muscle and adipose tissue endothelium. (PMID:25561514)
• Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms. (PMID:26428460)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcf15	ENSDARG00000067544
mus_musculus	Tcf15	ENSMUSG00000068079
rattus_norvegicus	Tcf15	ENSRNOG00000000012
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953

Paralogs (13): HAND1 (ENSG00000113196), TCF21 (ENSG00000118526), TWIST1 (ENSG00000122691), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Transcription factor 15 — Q12870 (reviewed: Q12870)

Alternative names: Class A basic helix-loop-helix protein 40, Paraxis, Protein bHLH-EC2

All UniProt accessions (1): Q12870

UniProt curated annotations — full annotation on UniProt →

Function. Early transcription factor that plays a key role in somitogenesis, paraxial mesoderm development and regulation of stem cell pluripotency. Essential for the mesenchymal to epithelial transition associated with somite formation. Required for somite morphogenesis, thereby regulating patterning of the axial skeleton and skeletal muscles. Required for proper localization of somite epithelium markers during the mesenchymal to epithelial transition. Also plays a key role in regulation of stem cell pluripotency. Promotes pluripotency exit of embryonic stem cells (ESCs) by priming ESCs for differentiation. Acts as a key regulator of self-renewal of hematopoietic stem cells (HSCs) by mediating HSCs quiescence and long-term self-renewal. Together with MEOX2, regulates transcription in heart endothelial cells to regulate fatty acid transport across heart endothelial cells. Acts by forming a heterodimer with another helix-loop-helix (bHLH) protein, such as TCF3/E12, that binds DNA on E-box motifs (5’-CANNTG-3’) and activates transcription of target genes.

Subunit / interactions. Heterodimer; efficient DNA binding requires dimerization with another bHLH protein, such as TCF3/E12. Interacts with MEOX2.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_004600* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (6 total): sequence conflict 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12870-F1	70.17	0.27

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MESENCHYMAL_TO_EPITHELIAL_TRANSITION, GOBP_ESTABLISHMENT_OF_EPITHELIAL_CELL_POLARITY, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_NEGATIVE_REGULATION_OF_STEM_CELL_DIFFERENTIATION, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_EXTRACELLULAR_MATRIX_ORGANIZATION

GO Biological Process (22): somitogenesis (GO:0001756), respiratory system process (GO:0003016), regulation of transcription by RNA polymerase II (GO:0006357), mesoderm development (GO:0007498), stem cell population maintenance (GO:0019827), developmental process (GO:0032502), post-anal tail morphogenesis (GO:0036342), ear development (GO:0043583), establishment of epithelial cell apical/basal polarity (GO:0045198), positive regulation of transcription by RNA polymerase II (GO:0045944), paraxial mesoderm development (GO:0048339), muscle organ morphogenesis (GO:0048644), skeletal system morphogenesis (GO:0048705), neuromuscular process controlling posture (GO:0050884), mesenchymal to epithelial transition (GO:0060231), negative regulation of hematopoietic stem cell differentiation (GO:1902037), regulation of extracellular matrix organization (GO:1903053), positive regulation of stem cell differentiation (GO:2000738), muscle organ development (GO:0007517), anterior/posterior pattern specification (GO:0009952), regulation of gene expression (GO:0010468), cell differentiation (GO:0030154)

GO Molecular Function (9): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), bHLH transcription factor binding (GO:0043425), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA binding (GO:0003677)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), RNA polymerase II transcription regulator complex (GO:0090575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
animal organ morphogenesis	2
transcription cis-regulatory region binding	2
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
system process	1
respiratory gaseous exchange by respiratory system	1
tissue development	1
multicellular organismal process	1
maintenance of cell number	1
biological_process	1
anatomical structure morphogenesis	1
sensory organ development	1
polarized epithelial cell differentiation	1
establishment of apical/basal cell polarity	1
establishment or maintenance of epithelial cell apical/basal polarity	1
establishment of epithelial cell polarity	1
positive regulation of DNA-templated transcription	1
mesoderm development	1
mesenchyme development	1
muscle organ development	1
skeletal system development	1
musculoskeletal movement	1
neuromuscular process	1
epithelial cell differentiation	1
hematopoietic stem cell differentiation	1
negative regulation of hematopoietic progenitor cell differentiation	1
regulation of hematopoietic stem cell differentiation	1
negative regulation of stem cell differentiation	1
extracellular matrix organization	1
regulation of cellular component organization	1
positive regulation of cell differentiation	1
stem cell differentiation	1
regulation of stem cell differentiation	1

Protein interactions and networks

STRING

1140 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCF15	MEOX2	P50222	829
TCF15	MKX	Q8IYA7	795
TCF15	FOXC2	Q99958	741
TCF15	CDH17	Q12864	736
TCF15	PAX1	P15863	689
TCF15	FOXC1	Q12948	638
TCF15	LFNG	Q8NES3	623
TCF15	MEOX1	P50221	622
TCF15	DSG3	P32926	596
TCF15	DSG1	Q02413	594
TCF15	ONECUT3	O60422	590
TCF15	DLL1	O00548	588
TCF15	EFNB2	P52799	586
TCF15	DYNC1I2	Q13409	582
TCF15	B4E171	B4E171	570

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TCF15	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
RUNX2	IGLL5	psi-mi:“MI:0914”(association)	0.350
TCF15	TCF4	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): TCF15 (Proximity Label-MS), TCF4 (Affinity Capture-MS), SPATA33 (Affinity Capture-MS), TCF15 (Affinity Capture-MS), TCF3 (Affinity Capture-MS), FAT3 (Affinity Capture-MS), APPBP2 (Affinity Capture-MS), AS3MT (Affinity Capture-MS), C1QBP (Affinity Capture-MS), TCF12 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), TCF15 (Affinity Capture-Western)

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A5A769, A5PJP1, A6NIN4, A6NJG2, A6NLJ0, C9JTQ0, O14492, O15370, O35182, O43541, O88940, P0DPE3, P28283, P58267, Q12870, Q14681, Q29RM6, Q2KJ18, Q53LP3, Q60539, Q60756, Q64124, Q6F5E0, Q6QNY0, Q6XD76, Q7RTU0, Q7RTU7, Q80WY3, Q80XF7, Q86Y97, Q8BY98, Q8K025, Q8N912, Q8NCU7, Q8WY41

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	36
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1047898	GRCh37/hg19 20p13(chr20:67778-974841)	Pathogenic

SpliceAI

196 predictions. Top by Δscore:

Variant	Effect	Δscore
20:609711:ACC:A	donor_gain	0.9900
20:609711:ACCC:A	donor_gain	0.9900
20:609712:CCC:C	donor_gain	0.9900
20:609712:CCCC:C	donor_gain	0.9900
20:609708:CTCA:C	donor_loss	0.9800
20:609709:T:TA	donor_loss	0.9800
20:609711:A:AC	donor_gain	0.9800
20:609711:A:C	donor_loss	0.9800
20:609711:AC:A	donor_gain	0.9800
20:609711:ACCCC:A	donor_gain	0.9800
20:609712:C:CC	donor_gain	0.9800
20:609712:C:G	donor_loss	0.9800
20:609712:CC:C	donor_gain	0.9800
20:609712:CCCCC:C	donor_gain	0.9800
20:609714:C:CA	donor_gain	0.9800
20:604664:CC:C	acceptor_gain	0.9500
20:604665:CC:C	acceptor_gain	0.9500
20:604662:CACC:C	acceptor_gain	0.9000
20:604661:CCACC:C	acceptor_gain	0.8600
20:604662:CACCC:C	acceptor_gain	0.8600
20:609040:T:TA	donor_gain	0.8100
20:604667:T:G	acceptor_loss	0.8000
20:604668:G:C	acceptor_loss	0.7800
20:609086:A:AC	donor_gain	0.7500
20:609087:C:CC	donor_gain	0.7500
20:604666:C:CC	acceptor_gain	0.7400
20:609326:G:A	donor_gain	0.6900
20:609082:TCC:T	donor_gain	0.6800
20:604663:ACC:A	acceptor_gain	0.6500
20:604664:CCC:C	acceptor_gain	0.6500

AlphaMissense

1253 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:609737:G:C	F167L	1.000
20:609737:G:T	F167L	1.000
20:609739:A:G	F167L	1.000
20:609876:A:T	I121N	0.999
20:609891:A:G	L116P	0.999
20:609908:C:A	K110N	0.999
20:609908:C:G	K110N	0.999
20:609942:A:G	I99T	0.999
20:609942:A:T	I99N	0.999
20:609962:G:C	F92L	0.999
20:609962:G:T	F92L	0.999
20:609964:A:G	F92L	0.999
20:609736:A:G	C168R	0.998
20:609867:A:G	L124P	0.998
20:609903:T:A	E112V	0.998
20:609904:C:T	E112K	0.998
20:609910:T:C	K110E	0.998
20:609912:G:A	S109F	0.998
20:609954:A:G	L95P	0.998
20:609963:A:G	F92S	0.998
20:609988:G:T	R84S	0.998
20:609995:C:A	E81D	0.998
20:609995:C:G	E81D	0.998
20:609997:C:T	E81K	0.998
20:609735:C:G	C168S	0.997
20:609736:A:T	C168S	0.997
20:609743:G:C	C165W	0.997
20:609744:C:T	C165Y	0.997
20:609745:A:G	C165R	0.997
20:609869:G:C	H123Q	0.997

dbSNP variants (sampled 300 via entrez): RS1000633007 (20:607028 G>T), RS1000858149 (20:606797 G>A), RS1000910486 (20:607132 T>C), RS1001191637 (20:608516 C>A), RS1001237846 (20:608491 A>T), RS1001240692 (20:608802 A>T), RS1002018263 (20:604271 A>G), RS1002064490 (20:603942 C>A,G), RS1002138111 (20:610135 C>A), RS1002436607 (20:604252 A>T), RS1002914335 (20:610606 C>T), RS1003128328 (20:611681 A>G), RS1003233603 (20:610864 T>C), RS1003266053 (20:611798 C>G), RS1003807319 (20:605574 C>T)

Disease associations

OMIM: gene MIM:601010 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003542_11	Night sleep phenotypes	8.000000e-08
GCST003542_24	Night sleep phenotypes	4.000000e-07
GCST008362_68	Birth weight	4.000000e-08
GCST010241_389	Apolipoprotein A1 levels	8.000000e-10
GCST010242_348	HDL cholesterol levels	1.000000e-12
GCST010244_376	Triglyceride levels	9.000000e-11
GCST90020025_1651	Waist-to-hip ratio adjusted for BMI	1.000000e-15
GCST90020026_95	Hip index	4.000000e-10
GCST90020027_322	Waist-hip index	2.000000e-15
GCST90020028_1334	Hip circumference adjusted for BMI	9.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
sodium arsenite	decreases expression	1
Chir 99021	affects cotreatment, increases expression	1
nilotinib	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Dabigatran	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Abacavir	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases expression	1
Catechin	affects cotreatment, increases expression	1
Fluorouracil	increases expression	1
Lead	decreases expression	1
Penicillins	affects cotreatment, increases expression	1
Phenytoin	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Streptomycin	affects cotreatment, increases expression	1
Thalidomide	decreases expression	1
Tretinoin	affects cotreatment, increases expression, decreases expression	1
Isotretinoin	decreases expression	1
Ethylene Glycol	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7B9	SEES3-1V human TCF15, clone1	Embryonic stem cell	Male
CVCL_A7C0	SEES3-1V human TCF15, clone2	Embryonic stem cell	Male
CVCL_A7C1	SEES3-1V human TCF15, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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