CTCF

Summary

CTCF (CCCTC-binding factor, HGNC:13723) is a protein-coding gene on chromosome 16q22.1, encoding Transcriptional repressor CTCF (P49711). Chromatin binding factor that binds to DNA sequence specific sites and regulates the 3D structure of chromatin. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms’ tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10664 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 422 total — 39 pathogenic, 47 likely-pathogenic (top 8% of genes corpus-wide)
• Regional missense constraint (gnomAD): 3 of 7 regions constrained (≈35% of expected missense variation)
• GTEx eGene: eQTL in 12 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 153
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 4 cancer types (inferred from mutation patterns)
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.20 (highly constrained)
• Transcription factor: yes — 185 downstream targets (CollecTRI)
• MANE Select transcript: NM_006565
• Interaction hub: 4,312 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13723
Approved symbol	CTCF
Name	CCCTC-binding factor
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FAP108, CFAP108
Ensembl gene	ENSG00000102974
Ensembl biotype	protein_coding
OMIM	604167
Entrez	10664

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 21 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000264010

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1

ENST00000264010, ENST00000401394, ENST00000566078, ENST00000642420, ENST00000642819, ENST00000642847, ENST00000642943, ENST00000643892, ENST00000644753, ENST00000644852, ENST00000644950, ENST00000645306, ENST00000645409, ENST00000645699, ENST00000646076, ENST00000646566, ENST00000646771, ENST00000885126, ENST00000885127, ENST00000921455, ENST00000921456, ENST00000921457, ENST00000921458, ENST00000921459, ENST00000921460, ENST00000961391, ENST00000961392, ENST00001034694, ENST00001135257

RefSeq mRNA: 5 — MANE Select: NM_006565 NM_001191022, NM_001363916, NM_001438968, NM_001438969, NM_006565

CCDS: CCDS10841, CCDS54029, CCDS86536

Canonical transcript exons

ENST00000264010 — 12 exons

Exon	Start	End
ENSE00000690280	67620697	67620817
ENSE00000690296	67621442	67621591
ENSE00000690297	67626555	67626715
ENSE00000690303	67629398	67629533
ENSE00000690304	67636690	67636851
ENSE00001251143	67628370	67628552
ENSE00001558712	67562526	67562724
ENSE00001645353	67611951	67612121
ENSE00001664803	67571148	67571264
ENSE00002242686	67610824	67611613
ENSE00003589627	67616745	67616878
ENSE00003822538	67637688	67639177

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 97.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.0806 / max 462.5095, expressed in 1820 samples.

Highest expression (Bgee): ventricular zone, ganglionic eminence, endometrium epithelium, cortical plate, thymus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CTCF is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Artery Tibial	eqtl	3.1e-11	+0.39	16:67566446:G:GTTGC
Nerve Tibial	eqtl	1.6e-07	+0.35	16:67572405:G:A
Brain Nucleus accumbens basal ganglia	eqtl	6.6e-07	+0.53	16:67626999:G:A
Heart Atrial Appendage	eqtl	2.2e-03	+0.32	16:68113049:C:T
Lung	eqtl	2.8e-03	+0.49	16:67279902:G:A
Brain Cerebellum	eqtl	3.5e-03	+0.29	16:67390509:T:A
Artery Aorta	eqtl	1.2e-02	+0.28	16:67540505:T:C
Brain Hippocampus	eqtl	1.8e-02	+0.39	16:67024711:T:G
Thyroid	eqtl	1.9e-02	+0.48	16:67610660:GGTT:G
Adipose Visceral Omentum	eqtl	2.6e-02	+0.25	16:67572405:G:A
Adrenal Gland	eqtl	3.6e-02	+0.61	16:66758632:T:A
Adipose Subcutaneous	eqtl	4.7e-02	-0.07	16:67657765:A:G

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
154662	38.1538	1818
154663	3.2324	1382
154661	1.6494	1026
154659	0.6968	459
154664	0.5179	228
154660	0.5003	260
154665	0.3300	138

Top tissues by expression

showing 100 of 299 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.27	gold quality
ganglionic eminence	UBERON:0004023	96.56	gold quality
endometrium epithelium	UBERON:0004811	96.48	gold quality
cortical plate	UBERON:0005343	96.45	gold quality
thymus	UBERON:0002370	96.39	gold quality
embryo	UBERON:0000922	95.60	gold quality
cerebellar vermis	UBERON:0004720	93.66	gold quality
paraflocculus	UBERON:0005351	92.94	gold quality
lymph node	UBERON:0000029	92.48	gold quality
trabecular bone tissue	UBERON:0002483	92.27	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.05	gold quality
bone marrow	UBERON:0002371	91.73	gold quality
upper leg skin	UBERON:0004262	91.53	gold quality
gluteal muscle	UBERON:0002000	91.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.34	gold quality
ileal mucosa	UBERON:0000331	91.33	gold quality
granulocyte	CL:0000094	91.31	gold quality
biceps brachii	UBERON:0001507	91.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.31	gold quality
islet of Langerhans	UBERON:0000006	91.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.22	gold quality
bone marrow cell	CL:0002092	91.19	gold quality
colonic mucosa	UBERON:0000317	91.11	gold quality
penis	UBERON:0000989	91.05	gold quality
skeletal muscle tissue	UBERON:0001134	91.01	gold quality
tonsil	UBERON:0002372	91.01	gold quality
deltoid	UBERON:0001476	90.69	gold quality
amniotic fluid	UBERON:0000173	90.65	gold quality
blood	UBERON:0000178	90.64	gold quality
buccal mucosa cell	CL:0002336	90.60	gold quality
oviduct epithelium	UBERON:0004804	90.59	gold quality
globus pallidus	UBERON:0001875	90.54	gold quality
medial globus pallidus	UBERON:0002477	90.53	gold quality
muscle tissue	UBERON:0002385	90.52	gold quality
urethra	UBERON:0000057	90.43	gold quality
skin of hip	UBERON:0001554	90.37	gold quality
triceps brachii	UBERON:0001509	90.32	gold quality
lateral globus pallidus	UBERON:0002476	90.26	gold quality
quadriceps femoris	UBERON:0001377	90.17	gold quality
leukocyte	CL:0000738	90.15	gold quality
muscle organ	UBERON:0001630	90.14	gold quality
skeletal muscle organ	UBERON:0014892	90.14	gold quality
vastus lateralis	UBERON:0001379	90.11	gold quality
fallopian tube	UBERON:0003889	90.00	gold quality
gastrocnemius	UBERON:0001388	89.98	gold quality
pancreatic ductal cell	CL:0002079	89.97	gold quality
muscle of leg	UBERON:0001383	89.95	gold quality
tibialis anterior	UBERON:0001385	89.90	gold quality
caecum	UBERON:0001153	89.89	gold quality
mononuclear cell	CL:0000842	89.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.85	gold quality
oral cavity	UBERON:0000167	89.82	gold quality
monocyte	CL:0000576	89.80	gold quality
bronchial epithelial cell	CL:0002328	89.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.80	gold quality
body of tongue	UBERON:0011876	89.80	gold quality
cerebellum	UBERON:0002037	89.75	gold quality
popliteal artery	UBERON:0002250	89.74	gold quality
tibial artery	UBERON:0007610	89.73	gold quality
cerebellar cortex	UBERON:0002129	89.64	gold quality
ectocervix	UBERON:0012249	89.62	gold quality
vermiform appendix	UBERON:0001154	89.61	gold quality
synovial joint	UBERON:0002217	89.60	gold quality
pharyngeal mucosa	UBERON:0000355	89.57	gold quality
cerebellar hemisphere	UBERON:0002245	89.56	gold quality
vagina	UBERON:0000996	89.52	gold quality
jejunum	UBERON:0002115	89.51	gold quality
tongue	UBERON:0001723	89.44	gold quality
hair follicle	UBERON:0002073	89.44	gold quality
mammalian vulva	UBERON:0000997	89.40	gold quality
pylorus	UBERON:0001166	89.37	gold quality
zone of skin	UBERON:0000014	89.36	gold quality
skin of abdomen	UBERON:0001416	89.36	gold quality
renal medulla	UBERON:0000362	89.35	gold quality
skin of leg	UBERON:0001511	89.32	gold quality
spleen	UBERON:0002106	89.31	gold quality
colonic epithelium	UBERON:0000397	89.27	gold quality
placenta	UBERON:0001987	89.21	gold quality
mucosa of transverse colon	UBERON:0004991	89.20	gold quality
urinary bladder	UBERON:0001255	89.19	gold quality
endometrium	UBERON:0001295	89.19	gold quality
middle frontal gyrus	UBERON:0002702	89.15	gold quality
rectum	UBERON:0001052	89.14	gold quality
epithelium of mammary gland	UBERON:0003244	89.11	gold quality
uterine cervix	UBERON:0000002	89.09	gold quality
epithelium of bronchus	UBERON:0002031	89.03	gold quality
mammary duct	UBERON:0001765	89.02	gold quality
pancreas	UBERON:0001264	89.01	gold quality
bronchus	UBERON:0002185	88.98	gold quality
female reproductive system	UBERON:0000474	88.96	gold quality
upper arm skin	UBERON:0004263	88.96	gold quality
endocervix	UBERON:0000458	88.95	gold quality
superior surface of tongue	UBERON:0007371	88.94	gold quality
aorta	UBERON:0000947	88.93	gold quality
lower esophagus mucosa	UBERON:0035834	88.93	gold quality
frontal pole	UBERON:0002795	88.86	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.86	gold quality
seminal vesicle	UBERON:0000998	88.85	gold quality
body of uterus	UBERON:0009853	88.81	gold quality
Brodmann (1909) area 10	UBERON:0013541	88.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.40
E-CURD-88	yes	4.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	64.8
Cerebellum	tissue	39.7	high
Corpus callosum	tissue	36.2
Hippocampus	tissue	35.1	medium
Nucleus accumbens	tissue	33.8
Tonsil	tissue	33.2	high
Caudate putamen	tissue	33.2
Bone marrow	tissue	32.5	high
Postcentral gyrus	tissue	31.8
Midbrain	tissue	29.9
Frontal cortex	tissue	29.5
Spinal cord	tissue	29.3
Thalamus	tissue	29.1
Superior colliculi	tissue	29.1
Olfactory bulb	tissue	28.9
Skeletal muscle	tissue	28.5	high
Substantia nigra	tissue	28.5
Periaqueductal gray	tissue	28.5
Choroid plexus	tissue	28.4
Hypothalamus	tissue	28.3
Putamen	tissue	27.9
Medulla oblongata	tissue	27.7
Hippocampal formation	tissue	27.5
Pons	tissue	27.2
Lymph node	tissue	27.1	high
Septum	tissue	27.1
Locus coeruleus	tissue	27.0
Parathyroid gland	tissue	26.6	high
Tongue	tissue	26.5
Ventral forebrain	tissue	26.0
Cerebral cortex	tissue	25.8	high
Occipital cortex	tissue	25.8
Somatosensory cortex	tissue	25.7
Motor cortex	tissue	25.4
Prefrontal cortex	tissue	25.0
Entorhinal cortex	tissue	24.7
Basal ganglia	tissue	24.6	medium
Retrosplenial cortex	tissue	24.0
Temporal cortex	tissue	23.4
Retrosplenial and cingulate cortex	tissue	23.1
Amygdala	tissue	22.8
Insular cortex	tissue	21.9
Spleen	tissue	21.4	high
Rectum	tissue	20.3	high
Ovary	tissue	19.6	high
Endometrium 1	tissue	19.5	high
Appendix	tissue	19.5	high
Placenta	tissue	19.2	high
Cervix	tissue	19.0	high
Smooth muscle	tissue	19.0	high
Fallopian tube	tissue	18.7	high
Thyroid gland	tissue	18.1	high
Colon	tissue	17.7	high
Liver	tissue	17.5	low
Stomach 1	tissue	17.2	high
Retina	tissue	17.0
Urinary bladder	tissue	17.0	high
Skin 1	tissue	16.8	high
Esophagus	tissue	16.8	high
Seminal vesicle	tissue	16.7	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Cerebellar cortex (48.9), Flocculonodular lobe (47.6), Vermis (45.3), Corpus callosum, genu (white matter) (44.2), Parieto-temporal junction (white matter) (43.7).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 185 targets:

Target	Regulation
ABCA2	Unknown
ACKR3	Unknown
ACTR3	Repression
ACVR1C	Unknown
AFM
AHCYL1	Unknown
AKT1	Repression
ALDH1A3	Repression
ANG	Unknown
ANKRD46	Unknown
APP	Activation
ARL2	Repression
ARSI
ASAP2	Unknown
ATN1	Unknown
ATXN7	Unknown
B4GALNT1	Unknown
BATF2	Unknown
BAX
BBC3	Unknown
BCL2L14	Repression
BCL6	Repression
BICD2	Unknown
BRCA1	Unknown
C1R	Unknown
C4B
CCL16	Unknown
CCND1	Unknown
CD34
CD74

JASPAR motifs

Motif	Name	Family
MA0139.1	CTCF	More than 3 adjacent zinc fingers
MA0139.2	CTCF	More than 3 adjacent zinc fingers
MA1929.1	CTCF	More than 3 adjacent zinc fingers
MA1929.2	CTCF	More than 3 adjacent zinc fingers
MA1930.1	CTCF	More than 3 adjacent zinc fingers
MA1930.2	CTCF	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:17512414, PMID:34326481

Upstream regulators (CollecTRI, top): BCL3, CTCF, EPAS1, FOXH1, NFKB1, PAX6, USF1, WT1, YY1

miRNA regulators (miRDB)

Targeting CTCF by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 121 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548P	99.98	72.25	3784
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-12136	99.98	72.81	5713
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
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-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.205, missense Z 4.85 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264010 splits into 7 regions with different missense tolerance; 3 are missense-constrained (≈35% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
16:67,610,833–67,611,298	148 / 194.9	0.76	no
16:67,611,299–67,611,346	2 / 18.8	0.11	yes (p 1.1e-04)
16:67,611,347–67,611,509	53 / 63.6	0.83	no
16:67,611,510–67,621,571	70 / 290.1	0.24	yes (p 3.4e-38)
16:67,621,572–67,629,428	81 / 184.3	0.44	no
16:67,629,429–67,637,825	157 / 172.9	0.91	no
16:67,637,826–67,637,869	5 / 24.5	0.20	yes (p 8.2e-05)
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map
DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): Caov-4 (-2.967), Capan-1 (-2.93), VCaP (-2.748), AsPC-1 (-2.684), EOL-1 (-2.676), IST-MES2 (-2.67), ONCO-DG-1 (-2.645), BT-12 (-2.614), COLO 201 (-2.611), GAMG (-2.592), KP-2 (-2.582), HUP-T3 (-2.578), DK-MG (-2.567), PC-14 (-2.557), Panc 10.05 (-2.556).

Literature-anchored findings (GeneRIF, showing 40)

• It’s proposed that Tsix and CTCF together establish a regulatable epigenetic switch for X-inactivation. (PMID:11743158)
• observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific “change of function” rather than complete “loss of function” (PMID:11782357)
• Insertional mutagenesis identified nucleosome positioning sequences (NPSs) allow the remarkably precise distribution of target sites for the chromatin insulator protein CTCF to nucleosome linker sequences in the H19 ICR. (PMID:11971967)
• Conserved CTCF insulator elements flank the mouse and human beta-globin loci. (PMID:11997516)
• Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involves interaction between the CTCF-complex and Smads (PMID:12099698)
• Loss of CTCF mRNA or protein in Wilms tumors does not predispose to de novo methylation of the maternal allele of H19 but leaves open the possibility that post-transcriptional loss of CTCF protein may account for some instances of loss of imprinting. (PMID:12203779)
• CTCF is a common determinant to different pathways of death signaling in immature B cells. (PMID:12524457)
• the insulator activity of CTCF apparently involves an HDAC-independent association with the nuclear matrix (PMID:12878173)
• CTCF binding at the human IGF2/H19 imprinting control region(ICR). CTCF binding at the IGF2/H19 ICR is insufficient to regulate expression of IGF2/H19 in many human tissues. (PMID:12960026)
• CTCF can be inactivated by somatic mutation and genetic or epigenetic silencing of the wild-type allele in individual cases of invasivene ductal breast cancer; loss of CTCF protein function may contribute to tumor heterogeneity (PMID:14503807)
• beta-globin locus control region HS5 contains enhancer-blocking (insulator) activity that is both CTCF and developmental stage dependent (PMID:14645507)
• CTCF has a role in tethering an insulator to subnuclear sites (PMID:14759373)
• CTCF regulates Pax6 transcription by binding to its repressor element, which in turn blocks the effect of the ectoderm enhancer resulting in the inhibition of P0 promoter activity. (PMID:15096508)
• The terminal domain is active in HeLa, HEK293 and COS-7 cell lines where it is both sufficient and necessary for silencing an SV40 core promoter. (PMID:15304340)
• novel mechanism for IGF2 imprinting regulation, that is, the reduction of CTCF expression in the control of IGF2 imprinting (PMID:15471867)
• CTCF plays a major role in IRAK2 transcription; EMSA revealed a CTCF-binding site within the mouse Irak2 promoter (PMID:15670593)
• point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation (PMID:15731119)
• CTCF is involved in the control of myeloid cell growth and differentiation (PMID:15941718)
• CTCF overexpression may have evolved as a compensatory mechanism to protect breast cancer cells from apoptosis, thus providing selective survival advantages to these cells. (PMID:15958555)
• chromatin loop organized by the CTCF-bound, differentially methylated region at the Igf2/H19 locus can be detected in mitosis (PMID:16107875)
• Data indicate that reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter mediates epigenetic regulation of this CT gene in lung cancer cells. (PMID:16140944)
• the Kaiso-CTCF interaction negatively regulates CTCF insulator activity (PMID:16230345)
• increased CTCF can repress EBNA2 transcription (PMID:16731911)
• CTCF is a multifunctional epigenetic regulator with a role in carcinogenesis (review) (PMID:16989720)
• this study reports the identification and characterization of an insulator from the herpes simplex virus-1 LAT intron region that functions via CTCF (PMID:17267480)
• Study describes 13,804 CTCF-binding sites in potential insulators of the human genome in primary human fibroblasts; most of these sequences are located far from the transcriptional start sites, with their distribution strongly correlated with genes (PMID:17382889)
• Results reveal that CTCF is a down stream target of stress-induced signaling cascades and it plays a significant anti-apoptotic role in regulation of stress-induced cellular responses in HCE and hematopoietic myeloid cells. (PMID:17583694)
• a small number of zinc fingers mediate strong binding of CTCF to DNA, and a single finger-DNA interaction controls binding at imprinted loci (PMID:17827499)
• CTCF is indeed a protein with multifunctional activity that plays a significant role in modulating signalling pathways to mediate insulin-induced ML-1 cell proliferation. (PMID:18021171)
• Band-shift analysis upon the nuclear fractions from HIV-1 resistant cells showed that CTCF protein bound to HIV-1 promoter and this binding prevented the formation of NF-kappaB/LTR complex. (PMID:18207574)
• description of cohesin-binding sites in the human genome; most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger protein required for transcriptional insulation (PMID:18235444)
• Study shows that the distribution of cohesins on mammalian chromosome arms is not driven by transcriptional activity, instead, cohesins are found at most CTCF sites and CTCF is required for cohesin localization to these sites. (PMID:18237772)
• The results suggest a model whereby both HLA-DRB1 and HLA-DQA1 loci can interact simultaneously with XL9, and describe a regulatory mechanism involving the alteration of the general chromatin conformation and their regulation by CTCF. (PMID:18347100)
• STAG1 (Scc3/SA1) subunit of cohesin interacts with the CCTC-binding factor CTCF bound to the c-myc insulator element. (PMID:18550811)
• Results decribethe loss IGF2/H19 imprinting,loss of heterozygosity of IGF2R and CTCF, and incidental H. pylori infections in laryngeal squamous cell carcinoma. (PMID:18604514)
• CTCF positions 20 nucleosomes around its binding sites across the human genome. (PMID:18654629)
• CTCF is required in a dose-dependent manner and is involved in cell cycle progression of alphabeta T cells in the thymus. (PMID:18923423)
• CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues. (PMID:19008940)
• mapped the genome-wide binding sites of CTCF in three cell types and identified significant binding of CTCF to the boundaries of repressive chromatin domains marked by H3K27me3 (PMID:19056695)
• intrinsic looping activity of CTCF sites can nullify locus control region function. (PMID:19074263)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctcf	ENSDARG00000056621
mus_musculus	Ctcf	ENSMUSG00000005698
rattus_norvegicus	Ctcf	ENSRNOG00000017674

Paralogs (36): ZNF302 (ENSG00000089335), ZNF184 (ENSG00000096654), ZNF574 (ENSG00000105732), ZBTB24 (ENSG00000112365), ZNF142 (ENSG00000115568), CTCFL (ENSG00000124092), ZNF473 (ENSG00000142528), ZNF827 (ENSG00000151612), ZNF689 (ENSG00000156853), ZNF208 (ENSG00000160321), ZNF91 (ENSG00000167232), ZNF526 (ENSG00000167625), ZNF764 (ENSG00000169951), ZNF747 (ENSG00000169955), ZNF282 (ENSG00000170265), ZNF160 (ENSG00000170949), ZNF497 (ENSG00000174586), ZBTB34 (ENSG00000177125), ZNF771 (ENSG00000179965), ZNF48 (ENSG00000180035), ZNF594 (ENSG00000180626), ZBTB37 (ENSG00000185278), ZFP92 (ENSG00000189420), ZNF107 (ENSG00000196247), ZNF729 (ENSG00000196350), ZNF569 (ENSG00000196437), ZNF420 (ENSG00000197050), ZNF785 (ENSG00000197162), ZNF665 (ENSG00000197497), ZNF181 (ENSG00000197841), ZNF347 (ENSG00000197937), ZNF84 (ENSG00000198040), ZBTB48 (ENSG00000204859), ZNF845 (ENSG00000213799), ZNF99 (ENSG00000213973), ZNF688 (ENSG00000229809)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109447) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 29 distinct phenotype terms.

Mouse phenotype (MP)	Records
thin ventricular wall	1
atelectasis	1
embryonic growth arrest	1
thymus hypoplasia	1
abnormal T cell differentiation	1
abnormal nervous system electrophysiology	1
abnormal lung interstitium morphology	1
absent inner cell mass	1
increased double-negative T cell number	1
decreased double-positive T cell number	1
decreased growth hormone level	1
abnormal T cell morphology	1
decreased CD4-positive, alpha-beta T cell number	1
decreased CD8-positive, alpha-beta T cell number	1
increased single-positive T cell number	1
decreased single-positive T cell number	1
abnormal neurite morphology	1
embryonic lethality at implantation	1
decreased embryo weight	1
abnormal ventricle myocardium morphology	1
thick myocardium	1
postnatal lethality, incomplete penetrance	1
neonatal lethality, complete penetrance	1
embryonic lethality during organogenesis, complete penetrance	1
absent trophectoderm	1

+4 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	Q08705	92.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ATP6V0D1-DT	ncRNA	101927837
CTCF-DT	ncRNA	107984813
AGRP	protein-coding	181
RIPOR1	protein-coding	79567
ATP6V0D1	protein-coding	9114
CARMIL2	protein-coding	146206
ACD	protein-coding	65057
PARD6A	protein-coding	50855
ENKD1	protein-coding	84080
C16orf86	protein-coding	388284

Protein

Protein identifiers

Transcriptional repressor CTCF — P49711 (reviewed: P49711)

Alternative names: 11-zinc finger protein, CCCTC-binding factor, CTCFL paralog

All UniProt accessions (5): A0A2R8Y595, A0A2R8Y6C1, A0A2R8Y6Z6, A0A2R8YFL0, P49711

UniProt curated annotations — full annotation on UniProt →

Function. Chromatin binding factor that binds to DNA sequence specific sites and regulates the 3D structure of chromatin. Binds together strands of DNA, thus forming chromatin loops, and anchors DNA to cellular structures, such as the nuclear lamina. Defines the boundaries between active and heterochromatic DNA via binding to chromatin insulators, thereby preventing interaction between promoter and nearby enhancers and silencers. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, binding within the H19 imprinting control region (ICR) mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Mediates interchromosomal association between IGF2/H19 and WSB1/NF1 and may direct distant DNA segments to a common transcription factory. Regulates asynchronous replication of IGF2/H19. Plays a critical role in gene silencing over considerable distances in the genome. Preferentially interacts with unmethylated DNA, preventing spreading of CpG methylation and maintaining methylation-free zones. Inversely, binding to target sites is prevented by CpG methylation. Plays an important role in chromatin remodeling. Can dimerize when it is bound to different DNA sequences, mediating long-range chromatin looping. Causes local loss of histone acetylation and gain of histone methylation in the beta-globin locus, without affecting transcription. When bound to chromatin, it provides an anchor point for nucleosomes positioning. Seems to be essential for homologous X-chromosome pairing. May participate with Tsix in establishing a regulatable epigenetic switch for X chromosome inactivation. May play a role in preventing the propagation of stable methylation at the escape genes from X-inactivation. Involved in sister chromatid cohesion. Associates with both centromeres and chromosomal arms during metaphase and required for cohesin localization to CTCF sites. Plays a role in the recruitment of CENPE to the pericentromeric/centromeric regions of the chromosome during mitosis. Acts as a transcriptional repressor binding to promoters of vertebrate MYC gene and BAG1 gene. Also binds to the PLK and PIM1 promoters. Acts as a transcriptional activator of APP. Regulates APOA1/C3/A4/A5 gene cluster and controls MHC class II gene expression. Plays an essential role in oocyte and preimplantation embryo development by activating or repressing transcription. Seems to act as tumor suppressor.

Subunit / interactions. Interacts with CHD8. Interacts with LLPH. Interacts with CENPE. Interacts with BRD2; promoting BRD2 recruitment to chromatin.

Subcellular location. Nucleus. Nucleoplasm. Chromosome. Centromere.

Tissue specificity. Ubiquitous. Absent in primary spermatocytes.

Post-translational modifications. Sumoylated on Lys-74 and Lys-689; sumoylation of CTCF contributes to the repressive function of CTCF on the MYC P2 promoter.

Disease relevance. Intellectual developmental disorder, autosomal dominant 21 (MRD21) [MIM:615502] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Additional MRD21 features include short stature, microcephaly, and developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The 11 zinc fingers are highly conserved among vertebrates, exhibiting almost identical amino acid sequences. Different subsets or combination of individual zinc fingers gives the ability to CTCF to recognize multiple DNA target sites.

Miscellaneous. More than 13'00 CTCF-binding sites in potential insulators were identified in the human genome.

Similarity. Belongs to the CTCF zinc-finger protein family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49711-1	1	yes
P49711-2	2

RefSeq proteins (5): NP_001177951, NP_001350845, NP_001425897, NP_001425898, NP_006556* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Zf-C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR050331	Zinc_finger_PRDM4/PRDM1/PRDM14	Family
IPR056438	Znf-C2H2_CTCF	Domain

Pfam: PF00096, PF23611

UniProt features (86 total): strand 24, helix 15, zinc finger region 11, sequence variant 9, modified residue 8, compositionally biased region 6, cross-link 4, turn 4, region of interest 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

21 structures by resolution:

PDB	Title	Method	Resolution (Å)
5KKQ	Homo sapiens CCCTC-binding factor (CTCF) ZnF3-7 and DNA complex structure	X-RAY DIFFRACTION	1.74
5YEG	Crystal structure of CTCF ZFs4-8-Hs5-1a complex	X-RAY DIFFRACTION	2
5K5I	Homo sapiens CCCTC-binding factor (CTCF) ZnF5-8 and DNA complex structure in space group …	X-RAY DIFFRACTION	2.19
5T00	Human CTCF ZnF3-7 and methylated DNA complex	X-RAY DIFFRACTION	2.19
8SST	ZnFs 1-7 of CCCTC-binding factor (CTCF) K365T Mutant Complexed with 23mer	X-RAY DIFFRACTION	2.19
5K5J	Homo sapiens CCCTC-binding factor (CTCF) ZnF5-8 and DNA complex structure in space group …	X-RAY DIFFRACTION	2.29
8SSS	ZnFs 1-7 of CCCTC-binding factor (CTCF) Complexed with 23mer	X-RAY DIFFRACTION	2.3
5YEH	Crystal structure of CTCF ZFs4-8-eCBS	X-RAY DIFFRACTION	2.33
5UND	Crystal Structure of CTCF(ZnF 4-10) With 28-mer DNA	X-RAY DIFFRACTION	2.55
6QNX	Structure of the SA2/SCC1/CTCF complex	X-RAY DIFFRACTION	2.7
5YEF	Crystal structure of CTCF ZFs2-8-Hs5-1aE	X-RAY DIFFRACTION	2.81
8SSU	ZnFs 3-11 of CCCTC-binding factor (CTCF) Complexed with 19mer DNA	X-RAY DIFFRACTION	2.89
5YEL	Crystal structure of CTCF ZFs6-11-gb7CSE	X-RAY DIFFRACTION	2.96
5K5H	Homo sapiens CCCTC-binding factor (CTCF) ZnF4-7 and DNA complex structure	X-RAY DIFFRACTION	3.11
8SSQ	ZnFs 3-11 of CCCTC-binding factor (CTCF) Complexed with 35mer DNA 35-4	X-RAY DIFFRACTION	3.12
5K5L	Homo sapiens CCCTC-binding factor (CTCF) ZnF6-8 and H19 sequence DNA complex structure	X-RAY DIFFRACTION	3.12
8SSR	ZnFs 3-11 of CCCTC-binding factor (CTCF) Complexed with 35mer DNA 35-20	X-RAY DIFFRACTION	3.14
5T0U	CTCF ZnF2-7 and DNA complex structure	X-RAY DIFFRACTION	3.2
7W1M	Cryo-EM structure of human cohesin-CTCF-DNA complex	ELECTRON MICROSCOPY	6.5
1X6H	Solution structures of the C2H2 type zinc finger domain of human Transcriptional …	SOLUTION NMR
2CT1	Solution Structure of the zinc finger domain of Transcriptional repressor CTCF protein	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49711-F1	59.45	0.01

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Zinc-coordinating DNA-binding domains, Cancer-related genes, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, Human disease related genes, Mental and behavioural disorders, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH supported · IF supported

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 (12)

Type	Positions
N-acetylmethionine	1
Phosphothreonine	289, 317, 374
Phosphoserine	402, 609, 610, 612
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	18, 219, 689
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo)	74

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-9943962	CHD6, CHD7, CHD8, CHD9 subfamily	curated
R-HSA-5619507	Activation of HOX genes during differentiation	—
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis	electronic
R-HSA-1266738	Developmental Biology	—

MSigDB gene sets: 715 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_MUSCLE_TISSUE_DEVELOPMENT, MORF_MBD4, MORF_SMC1L1, chr16q22, TTTGTAG_MIR520D, GEORGES_CELL_CYCLE_MIR192_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MORF_UBE2N, MORF_RAD21, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), chromosome segregation (GO:0007059), negative regulation of cell population proliferation (GO:0008285), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), epigenetic regulation of gene expression (GO:0040029), 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), regulation of centromeric sister chromatid cohesion (GO:0070602), protein localization to chromosome, centromeric region (GO:0071459), genomic imprinting (GO:0071514), chromatin looping (GO:0140588), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), positive regulation of macromolecule biosynthetic process (GO:0010557)

GO Molecular Function (15): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), transcription coregulator binding (GO:0001221), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), chromatin insulator sequence binding (GO:0043035), sequence-specific DNA binding (GO:0043565), chromatin loop anchoring activity (GO:0140587), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA binding (GO:0003677), chromatin binding (GO:0003682), protein binding (GO:0005515), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837)

GO Cellular Component (6): chromosome, centromeric region (GO:0000775), condensed chromosome (GO:0000793), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), chromosome (GO:0005694)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Activation of HOX genes during differentiation	1
CHD chromatin remodelers	1
Developmental Biology	1

GO top-level categories

55 GO namespaces:

Category	Terms
regulation of DNA-templated transcription	4
regulation of gene expression	4
transcription by RNA polymerase II	3
gene expression	3
DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription cis-regulatory region binding	2
chromatin DNA binding	2
binding	2
nuclear lumen	2
intracellular membraneless organelle	2
negative regulation of DNA-templated transcription	1
RNA biosynthetic process	1
cell cycle process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
chromatin remodeling	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
regulation of sister chromatid cohesion	1
centromeric sister chromatid cohesion	1
protein localization to chromosome	1
germ cell development	1
epigenetic programming of gene expression	1
chromatin organization	1
cellular component organization	1
regulation of RNA biosynthetic process	1
macromolecule biosynthetic process	1
positive regulation of biosynthetic process	1
regulation of macromolecule biosynthetic process	1
positive regulation of macromolecule metabolic process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription factor binding	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 regulator activity	1
transition metal ion binding	1
DNA binding	1
DNA-DNA tethering activity	1
nucleic acid binding	1
cation binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
chromosomal region	1
chromosome	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 22 of 39 annotations. The rest are phylogenetic / computational / electronic (IEA).

22 experimentally-supported GO terms:

GO term	NS	Evidence
chromatin looping	BP	direct assay
epigenetic regulation of gene expression	BP	mutant phenotype
genomic imprinting	BP	direct assay
negative regulation of DNA-templated transcription	BP	direct assay
negative regulation of cell population proliferation	BP	mutant phenotype
negative regulation of transcription by RNA polymerase II	BP	direct assay
positive regulation of DNA-templated transcription	BP	direct assay
positive regulation of gene expression	BP	mutant phenotype
positive regulation of transcription by RNA polymerase II	BP	direct assay
protein localization to chromosome, centromeric region	BP	mutant phenotype
chromosome, centromeric region	CC	direct assay
condensed chromosome	CC	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA-binding transcription factor activity	MF	direct assay
DNA-binding transcription repressor activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
chromatin insulator sequence binding	MF	direct assay
sequence-specific DNA binding	MF	direct assay
transcription cis-regulatory region binding	MF	direct assay
transcription coregulator binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 4,312 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTCF	IGF2	P01344	887
CTCF	RAD21	O60216	875
CTCF	SMC3	Q9UQE7	819
CTCF	WSB1	Q9Y6I7	779
CTCF	POU5F1	P31359	772
CTCF	NANOG	Q9H9S0	771
CTCF	WAPL	Q7Z5K2	763
CTCF	CHIA	Q9BZP6	756
CTCF	MYC	P01106	750
CTCF	MDFIC	Q9P1T7	744
CTCF	NIPBL	Q6KC79	743
CTCF	SOX2	P48431	740
CTCF	SIX5	Q8N196	716
CTCF	CHD8	Q9HCK8	702
CTCF	SMC1A	Q14683	676

IntAct

Human interaction partners of CTCF in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

28 partners by confidence:

Partner	Interaction type	MIscore	Records
RPL31	physical association	0.740	1
HDLBP	physical association	0.580	4
APP	physical association	0.560	3
TRAF2	physical association	0.560	3
ZMYM4	physical association	0.560	3
ZMYM6	physical association	0.560	3
KDM5B	physical association	0.520	8
CHD8	physical association	0.460	3
POU5F1	physical association	0.400	2
DNAJC21	physical association	0.400	1
RAD21	physical association	0.400	1
RPL36A	physical association	0.400	1
RRP1B	physical association	0.400	1
SMC1A	physical association	0.400	1
CHD1L	physical association	0.370	1
DDX17	physical association	0.370	1
HSPB9	physical association	0.370	1
MT-ND4	physical association	0.370	1
RALA	physical association	0.370	1
EIF3CL	association	0.350	1
POLRMT	association	0.350	1
SAP18	association	0.350	1
ZRANB2	association	0.350	1
FBXW7	proximity	0.270	4
SMARCA4	proximity	0.270	2
AKT1	proximity	0.270	1
EGFR	proximity	0.270	1
PTPN11	proximity	0.270	1

BioGRID (588 interactions; top human partners by supporting records): PARP1 (Affinity Capture-Western; 9 records), NPM1 (Affinity Capture-Western; 8 records), HDLBP (Two-hybrid; 6 records), POLR2A (Affinity Capture-Western; 5 records), SUZ12 (Affinity Capture-Western; 5 records), RPL13A (Affinity Capture-MS; 4 records), RPL14 (Affinity Capture-MS; 4 records), RPL31 (Two-hybrid; 4 records), SMAD3 (Co-fractionation; 4 records), YBX1 (Affinity Capture-MS; 4 records), CHD8 (Reconstituted Complex; 3 records), DDX5 (Affinity Capture-MS; 3 records), FBL (Affinity Capture-MS; 3 records), KIAA0020 (Affinity Capture-MS; 3 records), RAD51 (Affinity Capture-Western; 3 records)

SIGNOR signaling

10 signaling interactions:

A	Effect	B	Mechanism
BCL3	“down-regulates quantity by repression”	CTCF	“transcriptional regulation”
CTCF	“up-regulates quantity by expression”	APP	“transcriptional regulation”
CTCF	“down-regulates quantity by repression”	BCL6	“transcriptional regulation”
CTCF	“down-regulates quantity by repression”	MYC	“transcriptional regulation”
CTCF	“up-regulates quantity by expression”	RARRES1	“transcriptional regulation”
CTCF	“down-regulates quantity by repression”	TERT	“transcriptional regulation”
NFKB1	“down-regulates quantity by repression”	CTCF	“transcriptional regulation”
HDLBP	“up-regulates activity”	CTCF	binding
CTCF	“up-regulates quantity by expression”	MGAT5B	“transcriptional regulation”
ADNP	“down-regulates activity”	CTCF	relocalization

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
★ CTCF-PARP1-HIS-KPNA-LMNA-TOP complex	9	TOP2A, NPM1, CTCF, H2AC18, H2AZ1, KPNA1, KPNA3, LMNA, PARP1
CTCF-SMAD3-SMAD4 complex	3	SMAD3, SMAD4, CTCF
CTCF-SET complex	2	CTCF, SET
CTCF-nucleophosmin complex	2	CTCF, NPM1

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 4 cancer types — ALL, BRCA, HNSC, UCEC.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for CTCF: 422 ClinVar records (86 pathogenic / likely pathogenic); 1 CIViC cancer variant; 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	47
Uncertain significance	186
Likely benign	75
Benign	21

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 86 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
521287	NM_006565.4(CTCF):c.615_618del (p.Lys206fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
1325777	NM_006565.4(CTCF):c.1102C>T (p.Arg368Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
984936	NM_006565.4(CTCF):c.778_781del (p.Lys260fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1203833	NM_006565.4(CTCF):c.1343G>A (p.Arg448Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
280869	NM_006565.4(CTCF):c.610dup (p.Thr204fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
625526	NM_006565.4(CTCF):c.773_776del (p.Lys258fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
280753	NM_006565.4(CTCF):c.1670_1674del (p.Val556_Cys557insTer)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1254810	NM_006565.4(CTCF):c.677A>G (p.Tyr226Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3378409	NM_006565.4(CTCF):c.782-2A>T	Pathogenic	criteria provided, multiple submitters, no conflicts	2
562205	NM_006565.4(CTCF):c.848G>A (p.Arg283His)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
88636	NM_006565.4(CTCF):c.375dup (p.Val126fs)	Pathogenic	criteria provided, single submitter	2
88637	NM_006565.4(CTCF):c.1186dup (p.Arg396fs)	Pathogenic	criteria provided, single submitter	2
973091	NM_006565.4(CTCF):c.979T>C (p.Cys327Arg)	Pathogenic	criteria provided, single submitter	2
998024	NM_006565.4(CTCF):c.329dup (p.Gly111fs)	Pathogenic	criteria provided, single submitter	2
422876	NM_006565.4(CTCF):c.1814del (p.Lys605fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CTCF’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 858):

Position(s)	Effect	Δscore	Sites
16:67571146	acceptor_loss	1.0000	3
16:67571265	donor_loss	1.0000
16:67610822–67610823	acceptor_loss	1.0000	4
16:67616743–67616744	acceptor_loss	1.0000	6
16:67616879	donor_loss	1.0000	2
16:67620695–67620696	acceptor_loss	1.0000	6
16:67620818–67620819	donor_loss	1.0000	4
16:67626544	acceptor_gain	1.0000
16:67626553–67626554	acceptor_loss	1.0000	5
16:67626716–67626717	donor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9.67e-08

Disease associations

OMIM: gene MIM:604167 | disease phenotypes: MIM:615502

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
CTCF-related neurodevelopmental disorder	Definitive	Autosomal dominant	4

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
Clefting	green
DDG2P	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Severe microcephaly	green

Mondo (4): CTCF-related neurodevelopmental disorder (MONDO:0014213), desmoplastic/nodular medulloblastoma (MONDO:0016711), intellectual disability (MONDO:0001071), acute megakaryoblastic leukemia in down syndrome (MONDO:0020526)

Orphanet (4): CTCF-related neurodevelopmental disorder (Orphanet:363611), Desmoplastic/nodular medulloblastoma (Orphanet:251863), Acute megakaryoblastic leukemia in children with Down syndrome (Orphanet:99887), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

showing 60 of 153 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000059	Hypoplastic labia majora
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000396	Overfolded helix
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000540	Hypermetropia
HP:0000574	Thick eyebrow
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000592	Blue sclerae
HP:0000601	Hypotelorism
HP:0000637	Long palpebral fissure
HP:0000656	Ectropion
HP:0000664	Synophrys
HP:0000675	Macrodontia of permanent maxillary central incisor
HP:0000691	Microdontia
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors

GWAS associations

5 associations:

Study	Trait	p-value
GCST000288_10	HDL cholesterol	8e-16
GCST010002_165	Refractive error	2e-14
GCST90002382_371	Eosinophil percentage of white cells	1e-13
GCST010083_159	Hemoglobin levels	1e-10
GCST006257_4	Elevated fasting plasma glucose	5e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004509	hemoglobin measurement
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523233 (SINGLE PROTEIN)

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

K365T.

PharmGKB: 1 entry (CPIC guideline: no)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	Kd	1988	nM	CHEMBL3752910
5.70	ED50	1988	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149848: Binding affinity to human CTCF incubated for 45 mins by Kinobead based pull down assay	kd	1.9881	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, affects binding, affects reaction	4
Valproic Acid	affects cotreatment, decreases expression, affects expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression	2
Ozone	decreases expression, increases abundance, affects expression, affects cotreatment	2
Tretinoin	affects cotreatment, decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
uranyl acetate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects binding, affects reaction, affects expression	1
Arsenic Trioxide	affects methylation	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Butyrates	decreases response to substance	1
Caffeine	increases phosphorylation	1
Formaldehyde	decreases expression	1
Hydralazine	affects cotreatment, decreases expression	1
Phenolsulfonphthalein	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Tunicamycin	decreases expression	1
Uranium	affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4421277	Binding	Inhibition of CTCF in HUVEC assessed as reduction of CTCF transcriptional activity by genome-wide RNA-seq and ChlP-seq analysis	Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0U1	SEES3-1V human CTCF, clone1	Embryonic stem cell	Male
CVCL_A0U2	SEES3-1V human CTCF, clone2	Embryonic stem cell	Male
CVCL_A0U3	SEES3-1V human CTCF, clone3	Embryonic stem cell	Male
CVCL_HC72	HEK293 eGFP-CTCF	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 288 trials:

NCT	Phase	Status	Title
NCT02422056	Phase 4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	Phase 4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	Phase 4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	Phase 4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	Phase 4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00098319	Phase 3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	Phase 3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	Phase 3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	Phase 3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT02270736	Phase 3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02017964	Phase 2	COMPLETED	Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed, Non-metastatic Desmoplastic Medulloblastoma
NCT00004639	Phase 2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	Phase 2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	Phase 2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty
NCT02350803	Phase 2	COMPLETED	Does Use of Rigid Fixation After Removing Distraction Osteogenesis Device Reduce the Relapse?
NCT03412474	Phase 2	COMPLETED	Suprazygomatic Block in Cleft Palate Surgery in Children
NCT02304302	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01616953	Phase 1/2	COMPLETED	Cell Therapy for Craniofacial Bone Defects
NCT02247193	Phase 1/2	COMPLETED	Botulinum Toxin to Improve Cosmesis of Primary Cleft Lip Repair
NCT07734974	Phase 1/2	COMPLETED	Description of Pain in Pediatric Patients With Cleft Lip and Palate Undergoing Alveolar Grafting Using Two Surgical Strategies: Stem Cells and Autogenous Iliac Crest Bone (Pain Evaluation in Children Undergoing Alveolar Grafting: Stem Cells vs. Iliac Crest Bone)
NCT00097149	Not specified	COMPLETED	Systematic Pediatric Care for Oral Clefts - South America
NCT00285714	Not specified	UNKNOWN	3D Imaging of Hard and Soft Tissue in Orthognathic Surgery
NCT00340977	Not specified	COMPLETED	Svangerskap, Arv, Og Miljo (Pregnancy, Heredity and Environment)
NCT00423072	Not specified	COMPLETED	Middle Ear Pressure Disregulation in Cleft Palate Patients
NCT00584272	Not specified	COMPLETED	Retrospective Study on the Outcome of Cleft Palate Repair: Comparing US Surgical and Ethicon Suture Materials
NCT00773994	Not specified	COMPLETED	Pilot Study Evaluating Characteristic Closure Patterns of the Normal Velopharyngeal Portal
NCT00779961	Not specified	UNKNOWN	An Investigation for the Optimal Timing of a Cleft Palate Repair
NCT00829101	Not specified	COMPLETED	Articulation and Phonology in Children With Unilateral Cleft Lip and Palate
NCT00993551	Not specified	COMPLETED	Timing of Primary Surgery for Cleft Palate
NCT00993993	Not specified	COMPLETED	Relational Development in Children With Cleft Lips and Palates: Influence of the Waiting Period Prior to the First Surgical Intervention and the Parents’ Psychological Perception of the Abnormality
NCT01046591	Not specified	COMPLETED	Sleep and Behavior in Children With Cleft Palate
NCT01252264	Not specified	COMPLETED	FaceBase Biorepository
NCT01380171	Not specified	COMPLETED	Primary Palatoplasty in Pediatric Patients - A Retrospective Review of Surgical Outcomes
NCT01500109	Not specified	COMPLETED	Efficacy of Oral Versus Intravenous Acetaminophen for Primary Pediatric Cleft Palate Repair
NCT01535131	Not specified	COMPLETED	Furlow Palatoplasty With Tensor Tenopexy
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT01867632	Not specified	COMPLETED	Acellular Dermal Matrix in Primary Palatoplasty
NCT02329509	Not specified	COMPLETED	Evaluation of Facial Growth in Two Primary Protocols Used in the Surgical Treatment of Unilateral Cleft Lip and Palate Patients
NCT02415361	Not specified	COMPLETED	Follow Ups of Parents With Infants With Cleft Lip and Palate
NCT02583100	Not specified	COMPLETED	Improving Outcomes in Cleft Palate Surgery
NCT02595307	Not specified	UNKNOWN	Improving Informed Consent for Cleft Palate Repair
NCT02658318	Not specified	COMPLETED	Postoperative Complications After Cleft Palate Closure in Patients With Pierre Robin Sequence: Operative Considerations
NCT02688634	Not specified	WITHDRAWN	The Role of Antibiotic Prophylaxis in Cleft Palate and Velopharyngeal Insufficiency Repair
NCT02702869	Not specified	ENROLLING_BY_INVITATION	Allied Cleft & Craniofacial Quality-Improvement and Research Network (ACCQUIREnet)
NCT02900014	Not specified	COMPLETED	Validation of a Production Method of Stem Cell Isolated From the Nasal Cavity for an Innovative Cell Therapy of Cleft Palate
NCT03170505	Not specified	COMPLETED	Using of Acellular Dermal Matrix in Cleft Palatal Fistula and Compare With Use of Conchal Cartolage
NCT03537976	Not specified	UNKNOWN	Targeting Surgeons’ Decision-Making for Cleft Lip Surgery
NCT03572907	Not specified	WITHDRAWN	Use of Titanium Plate in Rhinoplasty in Patients With Cleft Lip and Palate : Aesthetic and Functional Impact.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CTCF across ~30M SureChEMBL compounds — explore on Sugi Predict.