SPIC

Summary

SPIC (Spi-C transcription factor, HGNC:29549) is a protein-coding gene on chromosome 12q23.2, encoding Transcription factor Spi-C (Q8N5J4). Controls the development of red pulp macrophages required for red blood cells recycling and iron homeostasis. It is a selective cancer dependency (DepMap: 11.1% of cell lines).

The protein encoded by this gene regulates the development of red pulp macrophages, which are necessary for iron homeostasis and the recycling of red blood cells.

Source: NCBI Gene 121599 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 33 total
• Cancer dependency (DepMap): dependent in 11.1% of screened cell lines
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_152323

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29549
Approved symbol	SPIC
Name	Spi-C transcription factor
Location	12q23.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC40611, SPI-C
Ensembl gene	ENSG00000166211
Ensembl biotype	protein_coding
OMIM	612568
Entrez	121599

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000551346

RefSeq mRNA: 1 — MANE Select: NM_152323 NM_152323

CCDS: CCDS9082

Canonical transcript exons

ENST00000551346 — 6 exons

Exon	Start	End
ENSE00001101045	101482792	101482900
ENSE00001101052	101477558	101477651
ENSE00001101055	101479582	101479694
ENSE00002374098	101476828	101476907
ENSE00002379201	101486344	101486997
ENSE00002417353	101475336	101475502

Expression profiles

Bgee: expression breadth broad, 43 present calls, max score 83.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2639 / max 152.4258, expressed in 43 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127605	0.2639	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	83.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.52	gold quality
lymph node	UBERON:0000029	66.93	gold quality
bone marrow cell	CL:0002092	57.48	gold quality
vermiform appendix	UBERON:0001154	53.35	gold quality
liver	UBERON:0002107	50.69	gold quality
caecum	UBERON:0001153	50.39	gold quality
tonsil	UBERON:0002372	48.75	gold quality
right lobe of liver	UBERON:0001114	48.18	gold quality
bone marrow	UBERON:0002371	45.24	gold quality
cortical plate	UBERON:0005343	45.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	44.36	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
granulocyte	CL:0000094	43.28	silver quality
lower lobe of lung	UBERON:0008949	42.78	silver quality
secondary oocyte	CL:0000655	42.57	gold quality
epithelium of nasopharynx	UBERON:0001951	42.20	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality
biceps brachii	UBERON:0001507	40.57	gold quality
myocardium	UBERON:0002349	40.45	gold quality
gingival epithelium	UBERON:0001949	40.43	gold quality
germinal epithelium of ovary	UBERON:0001304	40.33	gold quality
esophagus squamous epithelium	UBERON:0006920	40.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	40.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	81.90
E-ANND-3	no	2.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
ADM
CD5L	Activation
FCER1G
FCER2	Activation
IGH
IL4	Activation
MMP12	Activation
PREB
PRF1
SPI1
TFAP2A

JASPAR motifs

Motif	Name	Family
MA0687.1	SPIC	Ets-related
MA0687.2	SPIC	Ets-related

JASPAR matrix evidence (PMIDs): PMID:16887979

miRNA regulators (miRDB)

25 targeting SPIC, 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-3163	100.00	77.23	8605
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
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-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-6847-5P	97.93	66.74	1808

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• A protein interaction between SPI-C and STAT6 is the basis for a novel mechanism for regulation of IL4 induced gene expression. (PMID:16647686)
• Spi-C positively regulates RANKL-mediated osteoclast differentiation and function. (PMID:32341419)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	spic	ENSDARG00000012435
mus_musculus	Spic	ENSMUSG00000004359
rattus_norvegicus	Spic	ENSRNOG00000005720

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ELF4 (ENSG00000102034), ETV2 (ENSG00000105672), ERF (ENSG00000105722), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), SPDEF (ENSG00000124664), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), FLI1 (ENSG00000151702), GABPA (ENSG00000154727), ERG (ENSG00000157554), ETS2 (ENSG00000157557), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), FEV (ENSG00000163497), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Protein

Protein identifiers

Transcription factor Spi-C — Q8N5J4 (reviewed: Q8N5J4)

All UniProt accessions (1): Q8N5J4

UniProt curated annotations — full annotation on UniProt →

Function. Controls the development of red pulp macrophages required for red blood cells recycling and iron homeostasis. Transcription factor that binds to the PU-box, a purine-rich DNA sequence (5’-GAGGA[AT]-3’) that can act as a lymphoid-specific enhancer. Regulates VCAM1 gene expression.

Subunit / interactions. Binds DNA as a monomer.

Subcellular location. Nucleus.

Tissue specificity. Preferentially detected in fetal and adult spleen, lymph nodes and at lower levels in bone marrow and fetal liver.

Similarity. Belongs to the ETS family.

RefSeq proteins (1): NP_689536* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR046328	ETS_fam	Family

Pfam: PF00178

UniProt features (2 total): chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N5J4-F1	67.85	0.38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, FOSTER_TOLERANT_MACROPHAGE_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_BLASTOCYST_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT, LIAN_LIPA_TARGETS_3M, GARY_CD5_TARGETS_UP, chr12q23, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, CHEN_METABOLIC_SYNDROM_NETWORK

GO Biological Process (5): blastocyst development (GO:0001824), regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (7): 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 activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

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
in utero embryonic development	1
anatomical structure development	1
cellular developmental process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPIC	NIPSNAP3A	Q9UFN0	934
SPIC	NIPSNAP3B	Q9BS92	840
SPIC	LAMP1	P11279	581
SPIC	ABCA1	O95477	520
SPIC	HOOK3	Q86VS8	511
SPIC	HPX	P02790	401
SPIC	GATA6	P78327	400
SPIC	CPZ	Q66K79	385
SPIC	SLC40A1	Q9NP59	372
SPIC	NR1H3	Q13133	369
SPIC	ANO4	Q32M45	352
SPIC	CLEC4F	Q8N1N0	321
SPIC	GTSF1	Q8WW33	312
SPIC	SLC48A1	Q6P1K1	306
SPIC	VSIG10	Q8N0Z9	305

IntAct

17 interactions, top by confidence:

A	B	Type	Score
MEOX1	SPIC	psi-mi:“MI:0915”(physical association)	0.560
INTS11	SPIC	psi-mi:“MI:0915”(physical association)	0.560
NFE2L2	SPIC	psi-mi:“MI:0915”(physical association)	0.370
	SPIC	psi-mi:“MI:0915”(physical association)	0.370
CCL24	SPIC	psi-mi:“MI:0915”(physical association)	0.370
IFNA2	SPIC	psi-mi:“MI:0915”(physical association)	0.370
IL18	SPIC	psi-mi:“MI:0915”(physical association)	0.370
ECE1	SPIC	psi-mi:“MI:0915”(physical association)	0.370
SPIC	MEOX1	psi-mi:“MI:0915”(physical association)	0.000
SPIC	INTS11	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): SPIC (Two-hybrid), SPIC (Two-hybrid), SPIC (Two-hybrid), SPIC (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0FIN4, A6NI15, B1WBU4, D2HNW6, D4A7U2, O35906, O43734, P10914, P14316, P15314, P17433, P17947, P23570, P23906, P97303, P97432, Q01892, Q17RD7, Q1LY51, Q1RML4, Q3SZP0, Q4V7B1, Q501R9, Q505G8, Q5EBA3, Q5SUE8, Q66HA2, Q6AI12, Q6BDS1, Q6P3D7, Q6PKU1, Q6ZNC4, Q7TN83, Q8BSV3, Q8HWS3, Q8N5J4, Q8N7W2, Q8R4E0, Q8VHI4, Q90876

Diamond homologs: A0A1W2PQ73, A0JN51, A1A4L6, A1YF15, A1YG61, A1YG91, A2D4Z7, A2T737, A2T762, A3FEM2, A4GTP4, A8WFJ9, O00321, O01519, O35906, O70132, O70273, O95238, P01105, P10157, P11536, P13474, P14921, P15062, P17433, P17947, P18755, P18756, P19102, P19419, P20105, P27577, P28322, P28324, P29773, P29774, P29776, P32519, P41156, P41158

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

815 predictions. Top by Δscore:

Variant	Effect	Δscore
12:101477556:A:AG	acceptor_gain	1.0000
12:101477557:G:GG	acceptor_gain	1.0000
12:101477557:GAC:G	acceptor_gain	1.0000
12:101477557:GACGT:G	acceptor_gain	1.0000
12:101477648:CCAG:C	donor_loss	1.0000
12:101477649:CAG:C	donor_loss	1.0000
12:101477650:AG:A	donor_loss	1.0000
12:101477651:GGTAA:G	donor_loss	1.0000
12:101477653:T:A	donor_loss	1.0000
12:101482789:T:G	acceptor_gain	1.0000
12:101482789:TAGAA:T	acceptor_loss	1.0000
12:101482790:A:AG	acceptor_gain	1.0000
12:101482790:A:C	acceptor_loss	1.0000
12:101482791:G:GA	acceptor_gain	1.0000
12:101482791:GA:G	acceptor_gain	1.0000
12:101482791:GAAC:G	acceptor_gain	1.0000
12:101482791:GAACA:G	acceptor_gain	1.0000
12:101482900:GG:G	donor_loss	1.0000
12:101482901:GTAC:G	donor_loss	1.0000
12:101482902:T:G	donor_loss	1.0000
12:101475500:CCGG:C	donor_loss	0.9900
12:101475501:CGG:C	donor_loss	0.9900
12:101476860:A:G	acceptor_gain	0.9900
12:101477553:AACAG:A	acceptor_loss	0.9900
12:101477554:ACAG:A	acceptor_loss	0.9900
12:101477555:CAGAC:C	acceptor_loss	0.9900
12:101477556:A:C	acceptor_loss	0.9900
12:101477658:A:G	donor_gain	0.9900
12:101479695:G:GG	donor_gain	0.9900
12:101482791:GAA:G	acceptor_gain	0.9900

AlphaMissense

1640 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:101486484:T:A	W154R	1.000
12:101486484:T:C	W154R	1.000
12:101486418:T:A	W132R	0.999
12:101486418:T:C	W132R	0.999
12:101486443:T:C	F140S	0.999
12:101486449:T:C	F142S	0.999
12:101486465:A:C	K147N	0.999
12:101486465:A:T	K147N	0.999
12:101486476:C:A	A151D	0.999
12:101486485:G:C	W154S	0.999
12:101486486:G:C	W154C	0.999
12:101486486:G:T	W154C	0.999
12:101486487:G:A	G155R	0.999
12:101486487:G:C	G155R	0.999
12:101486515:T:C	M164T	0.999
12:101486516:G:A	M164I	0.999
12:101486516:G:C	M164I	0.999
12:101486516:G:T	M164I	0.999
12:101486520:T:C	Y166H	0.999
12:101486542:T:A	L173H	0.999
12:101486545:G:C	R174T	0.999
12:101486546:A:C	R174S	0.999
12:101486546:A:T	R174S	0.999
12:101486602:T:C	F193S	0.999
12:101486362:T:A	L113Q	0.998
12:101486374:T:C	L117P	0.998
12:101486420:G:C	W132C	0.998
12:101486420:G:T	W132C	0.998
12:101486442:T:C	F140L	0.998
12:101486444:T:A	F140L	0.998

dbSNP variants (sampled 300 via entrez): RS1000266836 (12:101478342 CTTTAA>C), RS1000468963 (12:101485299 G>T), RS1000496178 (12:101480449 T>C), RS1000597179 (12:101486258 T>A,C), RS1000632210 (12:101480182 C>A,T), RS1000688355 (12:101473385 C>A), RS1000698540 (12:101487255 C>A), RS1000977710 (12:101473822 G>T), RS1001108640 (12:101473972 T>C), RS1001209002 (12:101486939 G>A), RS1001417404 (12:101474192 C>A,T), RS1001647142 (12:101484838 A>C,G), RS1001783396 (12:101480852 T>C,G), RS1001841904 (12:101486848 T>A,G), RS1001865151 (12:101479268 A>C)

Disease associations

OMIM: gene MIM:612568 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002408_10	Response to methotrexate in juvenile idiopathic arthritis	5.000000e-06
GCST004627_143	Lymphocyte count	2.000000e-10
GCST004747_21	Lung cancer in never smokers	7.000000e-06
GCST006611_137	HDL cholesterol	9.000000e-12
GCST008156_74	Hip circumference adjusted for BMI	5.000000e-06
GCST010242_91	HDL cholesterol levels	3.000000e-08
GCST90002386_331	High light scatter reticulocyte percentage of red cells	2.000000e-09
GCST90002388_437	Lymphocyte count	5.000000e-14
GCST90002388_438	Lymphocyte count	4.000000e-23
GCST90002406_343	Reticulocyte fraction of red cells	2.000000e-09
GCST90002407_292	White blood cell count	1.000000e-17

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0004612	high density lipoprotein cholesterol measurement
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

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Arsenic	affects methylation	1
Demecolcine	increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Vincristine	increases 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_A6Q3	SEES3-1V human SPIC, clone1	Embryonic stem cell	Male
CVCL_A6Q4	SEES3-1V human SPIC, clone2	Embryonic stem cell	Male
CVCL_A6Q5	SEES3-1V human SPIC, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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