HIC1

Summary

HIC1 (HIC ZBTB transcriptional repressor 1, HGNC:4909) is a protein-coding gene on chromosome 17p13.3, encoding Hypermethylated in cancer 1 protein (Q14526). Transcriptional repressor.

This gene functions as a growth regulatory and tumor repressor gene. Hypermethylation or deletion of the region of this gene have been associated with tumors and the contiguous-gene syndrome, Miller-Dieker syndrome. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 3090 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 108 total
• Phenotypes (HPO): 18
• Transcription factor: yes — 22 downstream targets (CollecTRI)
• MANE Select transcript: NM_006497

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4909
Approved symbol	HIC1
Name	HIC ZBTB transcriptional repressor 1
Location	17p13.3
Locus type	gene with protein product
Status	Approved
Aliases	ZBTB29, ZNF901
Ensembl gene	ENSG00000177374
Ensembl biotype	protein_coding
OMIM	603825
Entrez	3090

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000322941, ENST00000399849, ENST00000571875, ENST00000571990, ENST00000574370, ENST00000576444, ENST00000619757, ENST00000966022, ENST00000966023

RefSeq mRNA: 2 — MANE Select: NM_006497 NM_001098202, NM_006497

CCDS: CCDS42229, CCDS42230

Canonical transcript exons

ENST00000619757 — 2 exons

Exon	Start	End
ENSE00003749761	2056671	2063241
ENSE00003841824	2055103	2055238

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 90.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6761 / max 306.0183, expressed in 1216 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158803	10.3885	1186
158804	7.2876	823

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	90.99	silver quality
stromal cell of endometrium	CL:0002255	89.93	gold quality
apex of heart	UBERON:0002098	89.10	gold quality
sural nerve	UBERON:0015488	88.39	gold quality
vena cava	UBERON:0004087	86.95	silver quality
right ovary	UBERON:0002118	86.74	gold quality
left ovary	UBERON:0002119	86.41	gold quality
left uterine tube	UBERON:0001303	86.38	gold quality
body of uterus	UBERON:0009853	86.10	gold quality
pericardium	UBERON:0002407	85.49	silver quality
omental fat pad	UBERON:0010414	85.09	gold quality
peritoneum	UBERON:0002358	85.04	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.43	gold quality
tendon of biceps brachii	UBERON:0008188	84.29	gold quality
endocervix	UBERON:0000458	83.69	gold quality
adenohypophysis	UBERON:0002196	83.68	gold quality
cardiac atrium	UBERON:0002081	83.60	gold quality
right atrium auricular region	UBERON:0006631	83.39	gold quality
myometrium	UBERON:0001296	83.25	gold quality
myocardium	UBERON:0002349	83.08	silver quality
lower esophagus muscularis layer	UBERON:0035833	82.93	gold quality
lower esophagus	UBERON:0013473	82.87	gold quality
metanephros cortex	UBERON:0010533	82.77	gold quality
ovary	UBERON:0000992	82.63	gold quality
heart left ventricle	UBERON:0002084	82.05	gold quality
cardiac ventricle	UBERON:0002082	81.83	gold quality
colonic epithelium	UBERON:0000397	81.79	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.46	gold quality
decidua	UBERON:0002450	81.33	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.14
E-MTAB-2983	no	166.94

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

22 targets.

Target	Regulation
ACKR3	Repression
ADRB2
ATOH1	Repression
CDKN1A	Unknown
CXCL14
E2F1	Repression
EFNA1	Repression
EPHA2	Repression
FGFBP1	Unknown
HIC1
IGF2
IL6
LRP8	Repression
MYC	Repression
RASSF1
SIRT1	Repression
SMARCA4
STAT3	Activation
TMPO
TP53
VEGFA	Repression
VLDLR	Repression

Upstream regulators (CollecTRI, top): E2F1, HIC1, SIRT1, TCF3, TP53

miRNA regulators (miRDB)

52 targeting HIC1, 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-4455	100.00	65.48	1587
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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
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-1468-3P	99.96	72.74	3797
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-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737

Literature-anchored findings (GeneRIF, showing 40)

• HIC-1 (HIC1) is a transcriptional repressor. However, in contrast to other BTB/POZ transcriptional repressors ( such as BCL6 or PLZF) it fails to recruit SMRT/NCoR-mSin3A/HDAC complexes via its BTB/POZ domain. (PMID:10611298)
• A new major alternative promoter of HIC1 (HIC-1) is conserved in the murine locus and positively regulated by TP53. (PMID:11073960)
• HIC1 recruits the corepressor CtBP (C-terminal binding protein) through a phylogenetically conserved GLDLSKK motif located in a central region of the protein. This motif is a variant of the “classical” PxDLSxK found in other CtBP-interacting proteins. (PMID:12052894)
• The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. (PMID:12052894)
• aberrant methylation of HIC1 may play a role in the pathogenesis of specific pediatric tumors (PMID:14506157)
• epigenetic silencing of HIC-1 may well contribute to the pathogenesis in the majority of medulloblastomas. (PMID:14656076)
• Inactivation of HIC1 by hypermethylation is associated with medulloblastoma pathogenesis (PMID:14688019)
• analysis of HIC1 consensus binding sequence and its DNA binding and repressive properties (PMID:15231840)
• In human osteosarcomas, hypermethylation of HIC1 is frequent only in tumors with p53 mutation (PMID:15488761)
• HIC1 p53-responsive element (HIC1.PRE) is necessary and sufficient to mediate induction of transcription by p53 (PMID:16301995)
• HIC1 is involved in a certain feedback regulation for p53 in tumor suppression through histone deacetylase. (review) (PMID:16386221)
• These data indicate that the intracellular amounts of HIC1 protein can modulate the level of the transcriptional stimulation of the genes regulated by canonical Wnt/beta-catenin signaling. (PMID:16724116)
• HIC1 interaction with the corepressor CtBP depends on a central leucine residue (PMID:16762039)
• HIC1 is a target of the class III deacetylase SIRT1 and identify a new posttranslational modification step in the P53-HIC1-SIRT1 regulatory loop. (PMID:17283066)
• Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in diffuse large B-cell lymphoma (PMID:17982487)
• ARID1A/BAF250A was identified as a new HIC1 partner. (PMID:19486893)
• Transcription factors were screened for regulation of a human HIC1 promoter reporter. Found that E2F1 strongly activates the full-length HIC1 promoter reporter. (PMID:19491197)
• The tumor suppressor HIC1 is implicated in the transcriptional regulation of the chemokine receptor CXCR7, a key player in the promotion of tumorigenesis in a wide variety of cell types. (PMID:19525223)
• Our data show the first valid clinical evidence of the deregulation of HIC1-SIRT1-p53 loop in lung tumorigenesis and prognosis (PMID:19649206)
• identify MTA1, a subunit of the NuRD complex, as a new HIC1 corepressor (PMID:20547755)
• Maternal genes FLNB, HIC1 and ZNF189 were strongly associated with risk of clefting. (PMID:20634891)
• Investigated the methylation of the SFRP2, P16, DAPK1, HIC1, and MGMT genes, as well as the mutation of amino acid codons 12 and 13 of the KRAS gene in normal and tumor tissue DNA of patients diagnosed with sporadic colorectal cancer. (PMID:20682398)
• This review highlights the role of HIC1 inactivation in solid tumours and particularly in leukaemia development (PMID:21104471)
• High frequency of methylation at MGMT, RASSFA, and HIC-1 was detected in colorectal carcinoma patients (PMID:21274674)
• Silencing of HIC1 and TOB1 expression is a common occurrence in gastric cancer and may contribute to the development and progression of the disease. (PMID:21533545)
• Promoter hypermethylation of tumor suppressor HIC1 is associated with prostate carcinoma. (PMID:22136354)
• loss of the regulation of this Eph pathway through HIC1 epigenetic silencing could be an important mechanism in the pathogenesis of epithelial cancers (PMID:22184117)
• early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the beta-2 adrenergic receptor (PMID:22194601)
• identify HIC1 as the first transcription factor in mammals able to recruit PRC2 to some target promoters through its interaction with Polycomb-like proteins. (PMID:22315224)
• Identify HIC1 hypermethylation in renal cell carcinoma as an independent predictor of reduced recurrence-free survival. (PMID:22327210)
• these results demonstrate that the activating acetylation to SUMOylation switch of HIC1 is favored by genotoxic stresses to regulate the DNA damage response. (PMID:22510409)
• A growth-regulatory role of HIC1 in the parathyroid glands and perturbed expression of HIC1 may represent an early event during tumor development. (PMID:22544915)
• Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer. (PMID:22552606)
• these results further demonstrate that HIC1 is a key player in the regulation of the DNA damage response. (PMID:23178572)
• Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. (PMID:23340301)
• epigenetic HIC1 inactivation, which is an early step in tumorigenesis, could contribute to the accumulation of DNA mutations through impaired DNA repair and thus favor tumorigenesis. (PMID:23417673)
• Reactivation of HIC1 suppressed cell migration and induced cell cycle arrest in the G0/G1 phase, as well as induced apoptosis in gastric cancer cells. (PMID:23769968)
• HIC1 interacts with and modulates the transcriptional activity of STAT3. (PMID:24067369)
• ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. (PMID:24076391)
• HIC1 silencing in triple-negative breast cancer drives progression through misregulation of LCN2. (PMID:24295734)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:66474	ENSDARG00000026453
danio_rerio	hic1	ENSDARG00000055493
mus_musculus	Hic1	ENSMUSG00000043099
rattus_norvegicus	Hic1	ENSRNOG00000057619

Paralogs (36): ZBTB32 (ENSG00000011590), SNAI2 (ENSG00000019549), PRDM1 (ENSG00000057657), PRDM6 (ENSG00000061455), ZNF76 (ENSG00000065029), PATZ1 (ENSG00000100105), MAZ (ENSG00000103495), ZBTB16 (ENSG00000109906), ZNF451 (ENSG00000112200), ZBTB45 (ENSG00000119574), ZNF410 (ENSG00000119725), SNAI1 (ENSG00000124216), ZNF384 (ENSG00000126746), ZBTB1 (ENSG00000126804), VEZF1 (ENSG00000136451), PRDM14 (ENSG00000147596), ZNF276 (ENSG00000158805), ZNF362 (ENSG00000160094), ZNF653 (ENSG00000161914), ZNF281 (ENSG00000162702), ZNF148 (ENSG00000163848), ZNF143 (ENSG00000166478), HIC2 (ENSG00000169635), PRDM10 (ENSG00000170325), ZNF296 (ENSG00000170684), ZNF692 (ENSG00000171163), ZNF575 (ENSG00000176472), ZBTB18 (ENSG00000179456), ZBTB42 (ENSG00000179627), ZBTB20 (ENSG00000181722), ZBTB7C (ENSG00000184828), SNAI3 (ENSG00000185669), ZFP91 (ENSG00000186660), MTF1 (ENSG00000188786), SCRT2 (ENSG00000215397), SCRT1 (ENSG00000261678)

Protein

Protein identifiers

Hypermethylated in cancer 1 protein — Q14526 (reviewed: Q14526)

Alternative names: Zinc finger and BTB domain-containing protein 29

All UniProt accessions (5): Q14526, I3L388, K7ENQ1, Q70SM2, V9GYA4

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor. Recognizes and binds to the consensus sequence ‘5-[CG]NG[CG]GGGCA[CA]CC-3’. May act as a tumor suppressor. Involved in development of head, face, limbs and ventral body wall. Involved in down-regulation of SIRT1 and thereby is involved in regulation of p53/TP53-dependent apoptotic DNA-damage responses. The specific target gene promoter association seems to be depend on corepressors, such as CTBP1 or CTBP2 and MTA1. In cooperation with MTA1 (indicative for an association with the NuRD complex) represses transcription from CCND1/cyclin-D1 and CDKN1C/p57Kip2 specifically in quiescent cells. Involved in regulation of the Wnt signaling pathway probably by association with TCF7L2 and preventing TCF7L2 and CTNNB1 association with promoters of TCF-responsive genes. Seems to repress transcription from E2F1 and ATOH1 which involves ARID1A, indicative for the participation of a distinct SWI/SNF-type chromatin-remodeling complex. Probably represses transcription of ACKR3, FGFBP1 and EFNA1.

Subunit / interactions. Self-associates. Interacts with HIC2. Interacts with CTBP1 and CTBP2. Interacts with TCF7L2 and ARID1A. Interacts with MTA1 and MBD3; indicative for an association with the NuRD complex. Interacts with SIRT1.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed with highest levels found in lung, colon, prostate, thymus, testis and ovary. Expression is absent or decreased in many tumor cells.

Post-translational modifications. Acetylated on several residues, including Lys-333. Lys-333 is deacetylated by SIRT1. Sumoylated on Lys-333 by a PIAS family member, which enhances interaction with MTA1, positively regulates transcriptional repression activity and is enhanced by HDAC4.

Domain organisation. The BTB domain inhibits the binding to a single consensus binding site, but mediates cooperative binding to multiple binding sites.

Miscellaneous. The HIC1 gene is frequently found epigenetically silenced or deleted in different types of solid tumors.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family. Hic subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14526-1	1	yes
Q14526-2	2

RefSeq proteins (2): NP_001091672, NP_006488* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096, PF00651

UniProt features (31 total): modified residue 6, mutagenesis site 6, zinc finger region 5, region of interest 4, compositionally biased region 4, chain 1, domain 1, cross-link 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14526-F1	50.95	0.00

Functional residue map

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

Post-translational modifications (7): 159, 237, 248, 333, 366, 704, 333

Mutagenesis-validated functional residues (6):

Position	Phenotype
244	abolishes interaction with ctbp1 and ctbp2. impairs transcriptional repression.
333	mimicks acetylation. impairs interaction with rbbp4 and mta1 and no effect on interaction with ctbp2. reduces transcript
333	abolishes sumoylation; impairs transcriptional repression activity.
335	impairs transcriptional repression activity. decreases interaction with mta1.
336	impairs k-333 acetylation; no effect on sumoylation. decreases interaction with mta1.
540	abolishes repression activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3232118	SUMOylation of transcription factors

MSigDB gene sets: 262 (showing top): GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, BENPORATH_ES_WITH_H3K27ME3, LI_PROSTATE_CANCER_EPIGENETIC, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, AP2_Q3, GGGTGGRR_PAX4_03, GOBP_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GTGCCTT_MIR506, GOBP_POSITIVE_REGULATION_OF_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, OHM_METHYLATED_IN_ADULT_CANCERS, GOBP_APOPTOTIC_SIGNALING_PATHWAY, WONG_ENDMETRIUM_CANCER_DN, BROWNE_HCMV_INFECTION_14HR_DN, TCF11_01

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), regulation of signal transduction (GO:0009966)

GO Molecular Function (10): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
transition metal ion binding	1
enzyme binding	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIC1	CTBP1	Q13363	960
HIC1	CTBP2	P56545	835
HIC1	MGMT	P16455	780
HIC1	RASSF1	Q9NS23	715
HIC1	YWHAE	P29360	704
HIC1	PAFAH1B1	P43034	669
HIC1	PITPNA	Q00169	662
HIC1	DNMT1	P26358	651
HIC1	CDKN2B	P42772	640
HIC1	CTNNB1	P35222	586
HIC1	CDKN2A	P42771	572
HIC1	DAPK1	P53355	570
HIC1	ATOH1	Q92858	565
HIC1	MNT	Q99583	555
HIC1	SIRT1	Q96EB6	549

IntAct

38 interactions, top by confidence:

A	B	Type	Score
HIC1	Ctbp1	psi-mi:“MI:0915”(physical association)	0.800
Ctbp1	HIC1	psi-mi:“MI:0915”(physical association)	0.800
HIC1	Ctbp1	psi-mi:“MI:0403”(colocalization)	0.800
Ctbp1	HIC1	psi-mi:“MI:0403”(colocalization)	0.800
TCF7L2	HIC1	psi-mi:“MI:0403”(colocalization)	0.610
HIC1	TCF7L2	psi-mi:“MI:0915”(physical association)	0.610
HIC1	CTBP1	psi-mi:“MI:0915”(physical association)	0.570
CTBP1	HIC1	psi-mi:“MI:0915”(physical association)	0.570
ARID1A	HIC1	psi-mi:“MI:0915”(physical association)	0.510
CTBP2	HIC1	psi-mi:“MI:0915”(physical association)	0.510
HIC1	CTBP2	psi-mi:“MI:0915”(physical association)	0.510
HIC1	ARID1A	psi-mi:“MI:0915”(physical association)	0.510
HIC1	Ctbp2	psi-mi:“MI:0915”(physical association)	0.510
Ctbp2	HIC1	psi-mi:“MI:0915”(physical association)	0.510
HIC1	CTNNB1	psi-mi:“MI:0915”(physical association)	0.460
CTNNB1	HIC1	psi-mi:“MI:0403”(colocalization)	0.460
Sirt1	HIC1	psi-mi:“MI:0915”(physical association)	0.400
HIC1		psi-mi:“MI:0915”(physical association)	0.400
SIRT1	HIC1	psi-mi:“MI:0915”(physical association)	0.400
HIC1	HIC1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (154): HIC1 (Co-localization), HIC1 (Co-localization), HIC1 (Co-localization), HIC1 (Co-localization), TCF7L2 (Reconstituted Complex), TCF7L2 (Affinity Capture-Western), HIC1 (Affinity Capture-Western), HIC1 (Reconstituted Complex), MECOM (Affinity Capture-Western), HIC1 (Affinity Capture-Western), MECOM (FRET), STAT3 (Affinity Capture-Western), HIC1 (Affinity Capture-Western), HIC1 (Affinity Capture-RNA), HIC1 (Affinity Capture-Western)

ESM2 similar proteins: A0A8I6AGW3, A2A9A2, A6NMB9, A8MYZ6, E9PZZ1, J3QK54, O02755, O02756, O35392, O35767, O60548, O70220, P05554, P17676, P21272, P28033, P35713, P42582, P49715, P49716, P52952, P53566, P58012, Q12952, Q13461, Q14526, Q60843, Q61345, Q63244, Q63250, Q6BEB4, Q6VFT5, Q6VFT6, Q6ZQN5, Q70KY4, Q8IU81, Q8MIP2, Q8NDY6, Q8R2I0, Q98937

Diamond homologs: A0JN76, A1L2U9, A1YEX3, A1YPR0, A2AAX3, B1WAZ8, B1WBS3, B1WBU4, B2RXF5, D3ZA50, O14867, O15062, O15156, O15209, O43167, O43298, O43829, O88282, O88939, O93567, O95365, P24278, P41182, P41183, P52739, P97302, P97303, Q08376, Q0IH98, Q0IJ29, Q0P4X6, Q0VCJ6, Q13105, Q14526, Q1H9T6, Q1L8W0, Q2T9Z7, Q3B725, Q3B7N9, Q3SWU4

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
E2F1	“up-regulates quantity by expression”	HIC1	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	ACKR3	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	E2F1	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	EFNA1	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	EPHA2	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	LRP8	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	VLDLR	“transcriptional regulation”
HIC1	“down-regulates activity”	MYC	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	STAT3	binding
HIC1	“down-regulates quantity by repression”	VEGFA	“transcriptional regulation”
HIC1	“down-regulates quantity by repression”	SIRT1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	96
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

277 predictions. Top by Δscore:

Variant	Effect	Δscore
17:2061618:CTCCT:C	acceptor_gain	1.0000
17:2061619:TCCT:T	acceptor_gain	1.0000
17:2061620:CCTC:C	acceptor_gain	1.0000
17:2061620:CCTCT:C	acceptor_loss	1.0000
17:2061621:CT:C	acceptor_gain	1.0000
17:2061622:TC:T	acceptor_loss	1.0000
17:2061623:C:CC	acceptor_gain	1.0000
17:2061624:T:A	acceptor_loss	1.0000
17:2061620:CCT:C	acceptor_gain	0.9900
17:2061621:CTC:C	acceptor_gain	0.9900
17:2061622:TCT:T	acceptor_gain	0.9900
17:2061623:C:G	acceptor_gain	0.9900
17:2061630:CA:C	acceptor_gain	0.9900
17:2061631:A:C	acceptor_gain	0.9900
17:2061631:A:T	acceptor_gain	0.9800
17:2056575:C:G	donor_gain	0.9700
17:2056581:G:T	donor_gain	0.9700
17:2061631:A:AC	acceptor_gain	0.9700
17:2062673:T:TA	donor_gain	0.9700
17:2061625:G:C	acceptor_gain	0.9600
17:2061625:G:GC	acceptor_gain	0.9600
17:2056394:G:GT	donor_gain	0.9500
17:2056587:G:T	donor_gain	0.9400
17:2061545:T:A	donor_gain	0.9400
17:2062617:AC:A	donor_gain	0.9300
17:2062618:CC:C	donor_gain	0.9300
17:2056587:G:GT	donor_gain	0.9200
17:2061630:C:CT	acceptor_loss	0.8900
17:2056581:G:GT	donor_gain	0.8800
17:2056556:GGC:G	donor_gain	0.8500

AlphaMissense

4582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:2057970:T:C	F446S	1.000
17:2058158:T:C	C509R	1.000
17:2058168:G:A	C512Y	1.000
17:2058242:T:C	C537R	1.000
17:2058243:G:A	C537Y	1.000
17:2058244:C:G	C537W	1.000
17:2058251:T:C	C540R	1.000
17:2058252:G:A	C540Y	1.000
17:2058253:C:G	C540W	1.000
17:2058263:T:C	F544L	1.000
17:2058264:T:C	F544S	1.000
17:2058265:C:A	F544L	1.000
17:2058265:C:G	F544L	1.000
17:2058290:C:A	H553N	1.000
17:2058290:C:G	H553D	1.000
17:2058292:C:A	H553Q	1.000
17:2058292:C:G	H553Q	1.000
17:2058302:C:G	H557D	1.000
17:2058304:C:A	H557Q	1.000
17:2058304:C:G	H557Q	1.000
17:2058320:T:C	F563L	1.000
17:2058322:C:A	F563L	1.000
17:2058322:C:G	F563L	1.000
17:2058326:T:C	C565R	1.000
17:2058327:G:A	C565Y	1.000
17:2058328:C:G	C565W	1.000
17:2058335:T:C	C568R	1.000
17:2058336:G:A	C568Y	1.000
17:2058337:C:G	C568W	1.000
17:2058347:T:C	F572L	1.000

dbSNP variants (sampled 300 via entrez): RS1000073456 (17:2059894 G>A), RS1000699005 (17:2055477 G>C), RS1000831836 (17:2053382 G>A,C), RS1001134941 (17:2053477 C>T), RS1001281747 (17:2057841 C>A), RS1001343387 (17:2059149 G>T), RS1001663987 (17:2063012 C>T), RS1001872779 (17:2055764 C>T), RS1002000765 (17:2061734 G>A), RS1002087914 (17:2057374 G>A,C), RS1003307384 (17:2054773 C>A,G), RS1003357063 (17:2055714 G>A,T), RS1003701724 (17:2060700 C>T), RS1003734286 (17:2060511 G>A), RS1003825867 (17:2053946 C>G,T)

Disease associations

OMIM: gene MIM:603825 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000112	Nephropathy
HP:0000177	Abnormal upper lip morphology
HP:0000286	Epicanthus
HP:0000348	High forehead
HP:0000463	Anteverted nares
HP:0000960	Sacral dimple
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001339	Lissencephaly
HP:0001510	Growth delay
HP:0001539	Omphalocele
HP:0001561	Polyhydramnios
HP:0001626	Abnormality of the cardiovascular system
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002353	EEG abnormality
HP:0003196	Short nose
HP:0004209	Clinodactyly of the 5th finger

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004603_245	Platelet count	4.000000e-15
GCST004607_67	Plateletcrit	4.000000e-24
GCST008367_17	Plasma anti-thyroglobulin and anti-thyroid peroxidase levels (bivariate analysis)	2.000000e-06
GCST010703_278	Brain morphology (MOSTest)	2.000000e-15
GCST90002392_4	Mean corpuscular volume	2.000000e-16
GCST90002397_727	Mean spheric corpuscular volume	3.000000e-25
GCST90002400_197	Plateletcrit	5.000000e-54
GCST90016667_29	Spleen volume	8.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	4
Tretinoin	increases expression	3
bisphenol F	increases methylation, increases expression, affects cotreatment	2
sodium arsenite	decreases expression, increases expression	2
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	affects cotreatment, affects expression	1
lead chloride	affects cotreatment, affects expression	1
cadmium sulfate	affects cotreatment, affects expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
CD 437	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Camptothecin	increases expression	1
Cisplatin	increases expression, affects cotreatment	1
Dactinomycin	affects cotreatment, increases expression	1
Demecolcine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XV66	HEK293 eGFP-HIC1	Transformed cell line	Female

Clinical trials (associated diseases)

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