SCX

Summary

SCX (scleraxis bHLH transcription factor, HGNC:32322) is a protein-coding gene on chromosome 8q24.3, encoding Basic helix-loop-helix transcription factor scleraxis (Q7RTU7). Plays an early essential role in mesoderm formation, as well as a later role in formation of somite-derived chondrogenic lineages.

Enables DNA-binding transcription activator activity, RNA polymerase II-specific and bHLH transcription factor binding activity. Contributes to E-box binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleus. Part of transcription regulator complex.

Source: NCBI Gene 642658 — RefSeq curated summary.

At a glance

• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_001080514

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32322
Approved symbol	SCX
Name	scleraxis bHLH transcription factor
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	bHLHa48, bHLHa41
Ensembl gene	ENSG00000260428
Ensembl biotype	protein_coding
OMIM	609067
Entrez	642658

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000567180, ENST00000942843

RefSeq mRNA: 1 — MANE Select: NM_001080514 NM_001080514

CCDS: CCDS43779

Canonical transcript exons

ENST00000567180 — 2 exons

Exon	Start	End
ENSE00002607285	144266453	144267180
ENSE00002615448	144268104	144268481

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 93.85.

FANTOM5 (CAGE): breadth broad, TPM avg 5.6516 / max 408.0696, expressed in 773 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
205398	5.6516	773

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	93.85	gold quality
quadriceps femoris	UBERON:0001377	90.29	silver quality
right lobe of thyroid gland	UBERON:0001119	89.68	gold quality
left lobe of thyroid gland	UBERON:0001120	88.28	gold quality
thyroid gland	UBERON:0002046	86.99	gold quality
calcaneal tendon	UBERON:0003701	85.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.53	gold quality
adenohypophysis	UBERON:0002196	84.24	gold quality
pituitary gland	UBERON:0000007	83.63	gold quality
cerebellar hemisphere	UBERON:0002245	83.49	gold quality
cerebellum	UBERON:0002037	83.46	gold quality
cerebellar cortex	UBERON:0002129	83.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.64	gold quality
ascending aorta	UBERON:0001496	82.05	gold quality
apex of heart	UBERON:0002098	82.02	gold quality
thoracic aorta	UBERON:0001515	81.67	gold quality
lower esophagus mucosa	UBERON:0035834	79.83	gold quality
skeletal muscle tissue	UBERON:0001134	79.23	gold quality
cerebellar vermis	UBERON:0004720	79.21	gold quality
heart left ventricle	UBERON:0002084	78.39	gold quality
mucosa of transverse colon	UBERON:0004991	77.87	gold quality
gastrocnemius	UBERON:0001388	77.36	gold quality
muscle of leg	UBERON:0001383	77.29	gold quality
descending thoracic aorta	UBERON:0002345	76.40	gold quality
primary visual cortex	UBERON:0002436	75.41	gold quality
muscle tissue	UBERON:0002385	73.87	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.73	gold quality
right uterine tube	UBERON:0001302	73.60	gold quality
right coronary artery	UBERON:0001625	73.57	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-38	yes	677.74
E-ANND-3	no	1.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
ACAN	Activation
ADRA1D
BMP4
COL1A1	Unknown
COL1A2	Activation
COL2A1	Activation
DAB1
HLA-E
SHBG	Activation
SMN1
SPP1	Activation
TF	Activation
TNMD	Unknown

Upstream regulators (CollecTRI, top): ETV4, MKX, SIX4, TCF15, TCF3

miRNA regulators (miRDB)

26 targeting SCX, 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-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-656-3P	100.00	72.15	2788
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-499B-5P	98.35	68.39	988
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-9900	96.06	65.48	557
HSA-MIR-4743-5P	88.08	64.31	91
HSA-MIR-4738-5P	87.41	60.29	56

Literature-anchored findings (GeneRIF, showing 14)

• Scleraxis was expressed in periodontal ligament cells, bone marrow cells, and gingival fibroblasts, and may play an important role in differentiation of periodontal ligament cells. (PMID:17129431)
• High glucose inhibited osteogenetic differentiation of periodontal ligament cells and up-regulated Scleraxis expression. (PMID:19087640)
• Scx and E47 might modulate the primary chondrogenesis by associating with the Sox9-related transcriptional complex, and by binding to the conserved E-box on Col2a1 promoter. (PMID:19828133)
• collagen type I and several T/L-related proteoglycans were upregulated in hMSC-Scx cells (PMID:21988170)
• Scleraxis thus appears to play a key role in the transcriptional regulation of type I collagen synthesis. (PMID:22796342)
• These studies identify an important role for Scx in regulating proteoglycans in embryonic and mature valve cells. (PMID:24157418)
• Abnormal upregulation of HIF-2alpha served as a key switch to direct TSPCs differentiation into osteochondral-lineage rather than teno-lineage. Notably, Scleraxis (Scx), an essential tendon specific transcription factor, was suppressed on constitutive activation of HIF-2alpha and mediated the effect of HIF-2alpha on TSPCs fate decision. (PMID:26851078)
• The transcription factor scleraxis is an important inducer of extracellular matrix gene expression in the heart that also control MMP2 expression. The scleraxis can exert control over both extracellular matrix synthesis and breakdown, and thus may contribute to matrix remodeling in wound healing and disease. (PMID:29750994)
• Scleraxis regulates epithelial-mesenchymal transition via direct transactivation of the Twist1 and Snai1 genes. (PMID:29906225)
• Scleraxis as a prognostic marker of myocardial fibrosis in hypertrophic cardiomyopathy (SPARC) study. (PMID:32027517)
• Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro. (PMID:32183051)
• The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases. (PMID:32708589)
• The transcription factor scleraxis differentially regulates gene expression in tenocytes isolated at different developmental stages. (PMID:32795590)
• Regulation of Cardiac Fibroblast GLS1 Expression by Scleraxis. (PMID:35563778)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	scxb	ENSDARG00000011635
danio_rerio	scxa	ENSDARG00000035695
mus_musculus	Scx	ENSMUSG00000034161
rattus_norvegicus	Scx	ENSRNOG00000021812
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), TCF15 (ENSG00000125878), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Basic helix-loop-helix transcription factor scleraxis — Q7RTU7 (reviewed: Q7RTU7)

Alternative names: Class A basic helix-loop-helix protein 41, Class A basic helix-loop-helix protein 48

All UniProt accessions (1): Q7RTU7

UniProt curated annotations — full annotation on UniProt →

Function. Plays an early essential role in mesoderm formation, as well as a later role in formation of somite-derived chondrogenic lineages.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Dimerizes and binds the E-box consensus sequence with E12.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_001073983* (*=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 (7 total): compositionally biased region 3, region of interest 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7RTU7-F1	68.68	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 161 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SERTOLI_CELL_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (38): mesoderm formation (GO:0001707), tissue homeostasis (GO:0001894), endochondral ossification (GO:0001958), chondrocyte differentiation (GO:0002062), heart valve morphogenesis (GO:0003179), heart valve formation (GO:0003188), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), cell differentiation (GO:0030154), collagen fibril organization (GO:0030199), BMP signaling pathway (GO:0030509), developmental process (GO:0032502), positive regulation of collagen biosynthetic process (GO:0032967), skeletal muscle cell differentiation (GO:0035914), tendon development (GO:0035989), tendon cell differentiation (GO:0035990), tendon formation (GO:0035992), deltoid tuberosity development (GO:0035993), negative regulation of apoptotic process (GO:0043066), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic skeletal system development (GO:0048706), Sertoli cell differentiation (GO:0060008), Sertoli cell development (GO:0060009), face morphogenesis (GO:0060325), regulation of cartilage development (GO:0061035), positive regulation of cartilage development (GO:0061036), sclerotome development (GO:0061056), cellular response to mechanical stimulus (GO:0071260), cellular response to cAMP (GO:0071320), cellular response to follicle-stimulating hormone stimulus (GO:0071372), cellular response to transforming growth factor beta stimulus (GO:0071560), positive regulation of gastrulation (GO:2000543), cellular response to BMP stimulus (GO:0071773)

GO Molecular Function (12): 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 (GO:0003677), bHLH transcription factor binding (GO:0043425), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	3
gene expression	3
transcription cis-regulatory region binding	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
anatomical structure formation involved in morphogenesis	2
regulation of DNA-templated transcription	2
regulation of gene expression	2
formation of primary germ layer	1
mesoderm morphogenesis	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
replacement ossification	1
endochondral bone morphogenesis	1
cartilage development	1
heart valve development	1
anatomical structure morphogenesis	1
heart valve morphogenesis	1
RNA biosynthetic process	1
transcription by RNA polymerase II	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
cellular developmental process	1
extracellular matrix organization	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
biological_process	1
positive regulation of biosynthetic process	1
positive regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
skeletal muscle tissue development	1
connective tissue development	1
tendon formation	1
tendon development	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCX	TNMD	Q9H2S6	952
SCX	MKX	Q8IYA7	749
SCX	PAX1	P15863	713
SCX	COL1A1	P02452	678
SCX	MSTN	O14793	583
SCX	ACVR1B	P36896	557
SCX	SOX9	P48436	555
SCX	SMAD2	Q15796	522
SCX	FMOD	Q06828	518
SCX	DCN	P07585	498
SCX	GDF7	Q7Z4P5	496
SCX	GDF5	P43026	491
SCX	SEMA3D	O95025	482
SCX	CAV3	P56539	470
SCX	SMAD3	P84022	468

IntAct

10 interactions, top by confidence:

A	B	Type	Score
NCK2	SCX	psi-mi:“MI:0915”(physical association)	0.560
MYF5	SCX	psi-mi:“MI:0915”(physical association)	0.560
TCF4	SCX	psi-mi:“MI:0915”(physical association)	0.560
NCK2	SCX	psi-mi:“MI:0915”(physical association)	0.000
SCX	MYF5	psi-mi:“MI:0915”(physical association)	0.000
SCX	TCF4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (6): SCX (Two-hybrid), SCX (Two-hybrid), SCX (Two-hybrid), SCX (Affinity Capture-Western), SCX (Two-hybrid), SCX (Two-hybrid)

ESM2 similar proteins: A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A2VDX9, A6NIN4, D3YXK1, G3UXB3, O15370, O15522, O35392, O70218, O70220, O89113, P0DPE3, P12980, P17542, P22091, P28283, P82976, Q04890, Q05916, Q05917, Q13461, Q14V87, Q15270, Q19A40, Q5T230, Q5VY09, Q63244, Q6F5E0, Q6SPE9, Q6SPF0, Q7RTU7, Q80WY3, Q8TD94, Q8WY41, Q8WZ71, Q91XV7, Q96Q04

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

1 interactions.

A	Effect	B	Mechanism
MKX	“up-regulates quantity by expression”	SCX	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

423 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144267177:GTTG:G	donor_gain	1.0000
8:144267174:A:T	donor_gain	0.9900
8:144267176:AGTTG:A	donor_loss	0.9900
8:144267178:TTGG:T	donor_loss	0.9900
8:144267179:TGG:T	donor_loss	0.9900
8:144267179:TGGT:T	donor_loss	0.9900
8:144267180:GGT:G	donor_loss	0.9900
8:144267181:G:GG	donor_gain	0.9900
8:144267181:GTG:G	donor_loss	0.9900
8:144267182:T:A	donor_loss	0.9900
8:144267183:GA:G	donor_loss	0.9900
8:144268102:A:AG	acceptor_gain	0.9800
8:144268103:G:GG	acceptor_gain	0.9800
8:144268103:GA:G	acceptor_gain	0.9800
8:144267173:GAAA:G	donor_gain	0.9700
8:144267178:TTG:T	donor_gain	0.9700
8:144267184:AGCA:A	donor_loss	0.9600
8:144268100:GCA:G	acceptor_loss	0.9600
8:144268101:CA:C	acceptor_loss	0.9600
8:144268101:CAG:C	acceptor_gain	0.9600
8:144268102:A:G	acceptor_loss	0.9600
8:144268102:A:T	acceptor_loss	0.9600
8:144268102:AGA:A	acceptor_gain	0.9600
8:144268103:G:A	acceptor_loss	0.9600
8:144268103:GAG:G	acceptor_gain	0.9600
8:144268103:GAGC:G	acceptor_gain	0.9500
8:144268103:GAGCA:G	acceptor_gain	0.9400
8:144267178:T:G	donor_gain	0.9300
8:144268099:TGCAG:T	acceptor_gain	0.9200
8:144267179:TG:T	donor_gain	0.9100

AlphaMissense

1282 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144266863:G:A	E84K	1.000
8:144266865:G:C	E84D	1.000
8:144266865:G:T	E84D	1.000
8:144266872:C:A	R87S	1.000
8:144266872:C:T	R87C	1.000
8:144266889:C:A	N92K	1.000
8:144266889:C:G	N92K	1.000
8:144266894:C:A	A94D	1.000
8:144266896:T:C	F95L	1.000
8:144266897:T:C	F95S	1.000
8:144266897:T:G	F95C	1.000
8:144266898:C:A	F95L	1.000
8:144266898:C:G	F95L	1.000
8:144266906:T:A	L98Q	1.000
8:144266906:T:C	L98P	1.000
8:144266915:T:C	L101P	1.000
8:144266918:T:A	I102N	1.000
8:144266918:T:C	I102T	1.000
8:144266918:T:G	I102S	1.000
8:144266945:T:A	L111H	1.000
8:144266948:C:A	S112Y	1.000
8:144266948:C:T	S112F	1.000
8:144266950:A:G	K113E	1.000
8:144266951:A:T	K113M	1.000
8:144266952:G:C	K113N	1.000
8:144266952:G:T	K113N	1.000
8:144266957:A:T	E115V	1.000
8:144266963:T:A	L117Q	1.000
8:144266963:T:C	L117P	1.000
8:144266969:T:C	L119P	1.000

dbSNP variants (sampled 300 via entrez): RS1000166670 (8:144267636 G>A,T), RS1000211146 (8:144264802 C>T), RS1000321051 (8:144264977 G>A), RS1001939112 (8:144265661 G>A,C), RS1001992080 (8:144265857 C>T), RS1002611951 (8:144268192 G>A,C), RS1002657672 (8:144268319 G>A,C), RS1003618856 (8:144267448 A>G), RS1003671269 (8:144267594 C>A,T), RS1004730189 (8:144264590 G>A,T), RS1005317602 (8:144266166 C>T), RS1005412284 (8:144266339 G>A), RS1006307498 (8:144265272 G>A,C), RS1006814922 (8:144265447 A>G,T), RS1006987613 (8:144267839 G>A,C)

Disease associations

OMIM: gene MIM:609067 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases expression, affects binding, increases activity, increases reaction, increases expression (+1 more)	2
aristolochic acid I	increases expression	1
mancozeb	decreases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
pinostrobin	increases expression	1
abrine	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Estradiol	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	increases expression	1
Thiram	increases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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