KLF4

Summary

KLF4 (KLF transcription factor 4, HGNC:6348) is a protein-coding gene on chromosome 9q31.2, encoding Krueppel-like factor 4 (O43474). Transcription factor; can act both as activator and as repressor.

This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required for normal development of the barrier function of skin. The encoded protein is thought to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. Mice lacking this gene have a normal appearance but lose weight rapidly, and die shortly after birth due to fluid evaporation resulting from compromised epidermal barrier function. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9314 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary palmoplantar keratoderma (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 21
• Clinical variants (ClinVar): 102 total
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• Transcription factor: yes — 133 downstream targets (CollecTRI)
• MANE Select transcript: NM_004235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6348
Approved symbol	KLF4
Name	KLF transcription factor 4
Location	9q31.2
Locus type	gene with protein product
Status	Approved
Aliases	EZF, GKLF
Ensembl gene	ENSG00000136826
Ensembl biotype	protein_coding
OMIM	602253
Entrez	9314

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 retained_intron

ENST00000374672, ENST00000411706, ENST00000420475, ENST00000493306, ENST00000497048, ENST00000610832, ENST00000850958

RefSeq mRNA: 2 — MANE Select: NM_004235 NM_001314052, NM_004235

CCDS: CCDS6770

Canonical transcript exons

ENST00000374672 — 5 exons

Exon	Start	End
ENSE00000983308	107487295	107488267
ENSE00001862452	107489168	107489769
ENSE00003482715	107488930	107489050
ENSE00003518983	107487028	107487192
ENSE00004282938	107484852	107485926

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.4990 / max 1450.3825, expressed in 1618 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101843	44.0958	1601
101844	1.4195	661
101841	1.3641	453
101842	1.3499	488
101839	0.1546	73
101840	0.0768	32
101838	0.0381	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	99.81	gold quality
skin of hip	UBERON:0001554	99.71	gold quality
penis	UBERON:0000989	99.64	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.60	gold quality
colonic mucosa	UBERON:0000317	99.53	gold quality
synovial joint	UBERON:0002217	99.51	gold quality
cervix squamous epithelium	UBERON:0006922	99.37	gold quality
upper arm skin	UBERON:0004263	99.36	gold quality
skin of abdomen	UBERON:0001416	99.33	gold quality
zone of skin	UBERON:0000014	99.18	gold quality
esophagus squamous epithelium	UBERON:0006920	99.17	gold quality
jejunal mucosa	UBERON:0000399	99.15	gold quality
mammalian vulva	UBERON:0000997	99.15	gold quality
squamous epithelium	UBERON:0006914	99.14	gold quality
skin of leg	UBERON:0001511	99.13	gold quality
pharyngeal mucosa	UBERON:0000355	99.11	gold quality
nipple	UBERON:0002030	99.10	gold quality
cervix epithelium	UBERON:0004801	99.09	gold quality
mucosa of stomach	UBERON:0001199	99.08	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.02	gold quality
epithelium of esophagus	UBERON:0001976	99.00	gold quality
urethra	UBERON:0000057	98.94	gold quality
gingiva	UBERON:0001828	98.85	gold quality
gingival epithelium	UBERON:0001949	98.82	gold quality
oral cavity	UBERON:0000167	98.80	gold quality
vena cava	UBERON:0004087	98.79	gold quality
amniotic fluid	UBERON:0000173	98.70	gold quality
cartilage tissue	UBERON:0002418	98.44	gold quality
saphenous vein	UBERON:0007318	98.37	gold quality
rectum	UBERON:0001052	98.33	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-CURD-55	yes	1436.47
E-GEOD-114530	yes	1381.01
E-MTAB-10287	yes	64.23
E-HCAD-4	yes	43.98
E-MTAB-9467	yes	34.30
E-MTAB-10553	yes	32.44
E-GEOD-135922	yes	27.53
E-GEOD-125970	yes	26.28
E-MTAB-9221	yes	25.78
E-HCAD-13	yes	20.62
E-CURD-112	yes	14.34
E-MTAB-8410	yes	12.43
E-GEOD-137537	yes	6.17
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

133 targets.

Target	Regulation
ACTA2	Unknown
ACTG2	Unknown
ADAM2
AGRP	Repression
AGTR1	Unknown
ALPI	Activation
ALPL
AQP3	Activation
ASS1	Activation
ATF3	Activation
BDKRB2	Activation
BIRC3	Unknown
BIRC5	Repression
CCL2	Repression
CCNB1	Repression
CCND1	Activation
CCND2
CCNE1	Repression
CD14	Activation
CD55	Activation
CD86	Unknown
CDH1	Activation
CDH17
CDH2
CDH5	Activation
CDK4
CDKN1A	Activation
CDKN1B	Activation
CDKN1C	Activation
CDKN2B	Activation

JASPAR motifs

Motif	Name	Family
MA0039.3	KLF4	Three-zinc finger Kruppel-related
MA0039.4	KLF4	Three-zinc finger Kruppel-related
MA0039.5	KLF4	Three-zinc finger Kruppel-related

JASPAR matrix evidence (PMIDs): PMID:18555785, PMID:28473536

Upstream regulators (CollecTRI, top): APC, CDX2, CEBPB, CTNNB1, DACH1, DNMT1, DNMT3A, EGR1, FOXC1, FOXO1, FOXO3, HDAC1, HDAC2, HDAC4, KLF4, KLF5, MAP2K5, MAPK7, MEF2A, MYC, NFKB, PPARA, PPARG, RARA, RUNX1, SNAI2, SOX9, SP1, SPI1, STAT1, STAT3, STAT6, TCF4, TP53, TP63, YBX1

miRNA regulators (miRDB)

157 targeting KLF4, 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-656-3P	100.00	72.15	2788
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-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-1229-3P	99.97	66.49	906

Literature-anchored findings (GeneRIF, showing 40)

• This study characterized the gene and promoter structures of the mouse KLF4 gene. (PMID:10556311)
• This paper examines the structure-function relationship of KLF4 in activating target gene expression and in suppressing growth. (PMID:10666450)
• This paper describes that KLF4 is transcriptionally activated by the p53 tumor suppressor after DNA damage and results in the transcriptional activation of the p21 cell cycle inhibitor gene. (PMID:10749849)
• This paper reports that KLF4 is regulated by the APC tumor suppressor in colorectal cancer cells through CDX2. (PMID:11521200)
• This paper describes the opposite effect of KLF4 and KLF5 on transcription of the KLF4 gene. (PMID:12087155)
• induction of GKLF mRNA and protein expression by interferon-gamma treatment was associated with reduction of ornithine decarboxylase (ODC) gene expression and enzyme activity in colon cancer HT-29 cells (PMID:12297499)
• KLF4 is an essential mediator of p53 in controlling G(1)/S progression of the cell cycle following DNA damage (PMID:12427745)
• down-regulation of gut-enriched Kruppel-like factor in esophageal squamous cancer (PMID:12439907)
• role in cell cycle regulation and epithelial differentiation (PMID:12581631)
• Over-expression of KLF4 in human colon cancer cells reduces tumorigenecity. (PMID:12776194)
• Regulation of A33 antigen expression by GKLF. (PMID:12853980)
• inactivation of KLF4 is one of the frequent steps towards bladder carcinogenesis (PMID:12901861)
• intestinal alkaline transactivation by Kruppel-like factor-4 is likely mediated through a critical region located within the proximal IAP promoter region (PMID:12919939)
• KLF4 is necessary for preventing the entry into mitosis following DNA damage (PMID:14627709)
• role of KLF4 in maintaining the integrity of the G2/M checkpoint following DNA damage (PMID:14627709)
• KLF4 can act to repress histidine decarboxylase gene expression by Sp1-dependent and -independent mechanisms (PMID:14670968)
• KLF4 is a tumor suppressor in colorectal cancer. (PMID:14724568)
• KLF4 is a novel regulator of u-PAR expression that drives the synthesis of u-PAR in the luminal surface epithelial cells of the colon (PMID:15031282)
• transactivation of Kruppel-like factor 4(KLF4) by butyrate appears to be mediated through interaction with a Sp1 transcription factor-binding domain on the promoter (PMID:15051827)
• KLF4 has a role in the aggressive phenotype of early-stage infiltrating ductal carcinoma (PMID:15102675)
• a longer isoform of gut-enriched Kruppel-like factor 4 (GKLF) we term GKLFa interacts with the CD11d promoter (PMID:15561714)
• KLF4 can function in the nucleus to induce squamous epithelial dysplasia. (PMID:15674344)
• A review article that summarizes the mechanisms by which KLF4 and KLF5 regulate cell proliferation. (PMID:15740636)
• Promoter hypermethylation and hemizygous deletion contributed to the down-regulation of KLF4 expression and the induction of apoptosis contributed to the antitumor activity of KLF4; alteration of KLF4 expression plays a role in gastric cancer development. (PMID:15805274)
• KLF4 is both necessary and sufficient in preventing centrosome amplification following gamma-radiation-induced DNA damage. (PMID:15806166)
• the cross talk of KLF4 and beta-catenin plays a critical role in homeostasis of the normal intestine as well as in tumorigenesis of colorectal cancers. (PMID:16507986)
• cGMP-dependent protein kinase expression is regulated by Rho and Kruppel-like transcription factor-4 (PMID:16632465)
• KLF4 may be an important determinant of cell fate following gamma-radiation-induced DNA damage. (PMID:17016435)
• KLF4 exerts a global inhibitory effect on macromolecular biosynthesis that is beyond its established role as a cell cycle inhibitor. (PMID:17017123)
• KLF-4 and AP-2 is regulating the activity of the hSMVT promoter in the intestine and provide direct in vivo confirmation of hSMVT promoter activity. (PMID:17135299)
• Kruppel-like factor 4 as a novel regulator of endothelial activation in response to pro-inflammatory stimuli. (PMID:17339326)
• A review article that summarizes the biological and pathobiological functions in the intestinal epithelium. (PMID:17508399)
• Genetic and epigenetic alterations of the KLF4 gene might play a minor role in gastric carcinogenesis. (PMID:17614846)
• This study reports that haploinsufficiency of Klf4 gene in transgenic mice with targeted deletion of one of the Klf4 alleles promotes intestinal tumorigenesis when crossbred with the ApcMin mice. (PMID:17671182)
• analysis of SNPs, located in the KLF2, KLF4 and KLF5 gene did not show an association with Type 2 diabetes in this French population (PMID:17688680)
• KLF4 is a critical regulator in the transcriptional network controlling monocyte differentiation. (PMID:17762869)
• KLF4 might function as an activator or repressor of transcription depending on whether it interacts with co-activators such as p300 and CREB-binding protein or co-repressors such as HDAC3. (PMID:17908689)
• Data show that human testis strongly expresses KLF4 and they were localized to nuclei of round spermatids during normal spermatogenesis stages II-IV. (PMID:17932114)
• Transient transfection of Kruppel-like factor 4 suppressed LDLR, steroidogenic acute regulatory protein, and CYP11A (PMID:18056793)
• Using ectopic expression of Oct4, Sox2, Klf4 and Myc, we have derived iPS cells from fetal, neonatal and adult human primary cells (PMID:18157115)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	klf4	ENSDARG00000079922
mus_musculus	Klf4	ENSMUSG00000003032
rattus_norvegicus	Klf4	ENSRNOG00000016299
drosophila_melanogaster	luna	FBGN0040765

Paralogs (22): KLF6 (ENSG00000067082), KLF8 (ENSG00000102349), KLF5 (ENSG00000102554), KLF1 (ENSG00000105610), KLF3 (ENSG00000109787), KLF7 (ENSG00000118263), KLF12 (ENSG00000118922), KLF9 (ENSG00000119138), KLF2 (ENSG00000127528), KLF16 (ENSG00000129911), KLF10 (ENSG00000155090), KLF15 (ENSG00000163884), SP8 (ENSG00000164651), KLF13 (ENSG00000169926), SP7 (ENSG00000170374), KLF17 (ENSG00000171872), KLF11 (ENSG00000172059), SP6 (ENSG00000189120), SP5 (ENSG00000204335), SP9 (ENSG00000217236), KLF14 (ENSG00000266265), KLF18 (ENSG00000283039)

Protein

Protein identifiers

Krueppel-like factor 4 — O43474 (reviewed: O43474)

Alternative names: Epithelial zinc finger protein EZF, Gut-enriched krueppel-like factor

All UniProt accessions (3): A0A087X0S4, O43474, B7ZBT2

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor; can act both as activator and as repressor. Binds the 5’-CACCC-3’ core sequence. Binds to the promoter region of its own gene and can activate its own transcription. Regulates the expression of key transcription factors during embryonic development. Plays an important role in maintaining embryonic stem cells, and in preventing their differentiation. Required for establishing the barrier function of the skin and for postnatal maturation and maintenance of the ocular surface. Involved in the differentiation of epithelial cells and may also function in skeletal and kidney development. Contributes to the down-regulation of p53/TP53 transcription.

Subunit / interactions. Interacts with POU5F1/OCT4 and SOX2. Interacts with MUC1 (via the C-terminal domain). Interacts with MEIS2 isoform 4 and PBX1 isoform PBX1a. Interacts with ZNF296. Interacts with GLIS1. Interacts with BTRC; this interaction leads to KLF4 ubiquitination and subsequent degradation. Interacts with IPO7; the interaction facilitates nuclear translocation of KLF4 in dental papilla cells. Interacts with FBXO32.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Ubiquitinated. ‘Lys-48’-linked ubiquitinated and targeted for proteasomal degradation by the SCF(BTRC) E3 ubiquitin-protein ligase complex, thereby negatively regulating cell pluripotency maintenance and embryogenesis. Ubiquitinated in a FBXO32-dependent manner, leading to proteasomal degradation. Polyglutamylated by TTLL1 and TTLL4 at Glu-411, which inhibits KLF4 binding with E3 ligase component BTRC, thereby impeding ubiquitination. Deglutamylated by CCP1 and CCP6; deglutamylation promotes KLF4 ubiquitination. KLF4 glutamylation state plays a critical role in the regulation of its function in cell reprogramming, pluripotency maintenance and embryogenesis.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

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

Isoforms (5)

UniProt ID	Names	Canonical?
O43474-3	1	yes
O43474-1	2
O43474-4	3
O43474-5	4, 1a
O43474-6	5

RefSeq proteins (2): NP_001300981, NP_004226* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (31 total): splice variant 6, sequence conflict 5, strand 4, zinc finger region 3, helix 3, region of interest 3, sequence variant 2, modified residue 2, chain 1, cross-link 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6VTX	X-RAY DIFFRACTION	2.14

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43474-F1	50.10	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 (3): 32, 254, 411

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-422085	Synthesis, secretion, and deacylation of Ghrelin
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-9617828	FOXO-mediated transcription of cell cycle genes
R-HSA-9764790	Positive Regulation of CDH1 Gene Transcription
R-HSA-1266738	Developmental Biology
R-HSA-212436	Generic Transcription Pathway
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9614085	FOXO-mediated transcription
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 744 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, RRAGTTGT_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, E2F4DP1_01, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (57): negative regulation of transcription by RNA polymerase II (GO:0000122), defense response to tumor cell (GO:0002357), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), mesodermal cell fate determination (GO:0007500), negative regulation of cell population proliferation (GO:0008285), epidermal cell differentiation (GO:0009913), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of muscle hyperplasia (GO:0014740), negative regulation of angiogenesis (GO:0016525), stem cell population maintenance (GO:0019827), post-embryonic camera-type eye development (GO:0031077), positive regulation of telomere maintenance (GO:0032206), negative regulation of interleukin-8 production (GO:0032717), negative regulation of heterotypic cell-cell adhesion (GO:0034115), somatic stem cell population maintenance (GO:0035019), post-embryonic hemopoiesis (GO:0035166), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of nitric oxide biosynthetic process (GO:0045429), fat cell differentiation (GO:0045444), regulation of cell differentiation (GO:0045595), 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), positive regulation of hemoglobin biosynthetic process (GO:0046985), negative regulation of smooth muscle cell proliferation (GO:0048662), regulation of axon regeneration (GO:0048679), epidermis morphogenesis (GO:0048730), negative regulation of inflammatory response (GO:0050728), positive regulation of protein metabolic process (GO:0051247), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), canonical Wnt signaling pathway (GO:0060070), negative regulation of response to cytokine stimulus (GO:0060761), establishment of skin barrier (GO:0061436), cellular response to hydrogen peroxide (GO:0070301), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to retinoic acid (GO:0071300), cellular response to growth factor stimulus (GO:0071363), cellular response to laminar fluid shear stress (GO:0071499)

GO Molecular Function (21): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), obsolete RNA polymerase II sequence-specific DNA-binding transcription factor recruiting activity (GO:0001010), transcription coregulator binding (GO:0001221), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), zinc ion binding (GO:0008270), chromatin DNA binding (GO:0031490), phosphatidylinositol 3-kinase regulator activity (GO:0035014), histone deacetylase binding (GO:0042826), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), lncRNA binding (GO:0106222), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (8): chromatin (GO:0000785), euchromatin (GO:0000791), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829), microtubule cytoskeleton (GO:0015630), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Developmental Biology	2
Adipogenesis	1
Peptide hormone metabolism	1
FOXO-mediated transcription	1
Regulation of CDH1 Gene Transcription	1
RNA Polymerase II Transcription	1
Metabolism of proteins	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
gene expression	2
regulation of gene expression	2
post-embryonic development	2
chromatin	2
chromatin binding	2
negative regulation of DNA-templated transcription	1
response to tumor cell	1
defense response	1
DNA-templated transcription	1
cell fate determination	1
mesodermal cell fate commitment	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
epidermis development	1
epithelial cell differentiation	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of muscle hyperplasia	1
negative regulation of muscle adaptation	1
muscle hyperplasia	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
multicellular organismal process	1
maintenance of cell number	1
camera-type eye development	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
negative regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

89 interactions, top by confidence:

A	B	Type	Score
KLF4	DVL3	psi-mi:“MI:0915”(physical association)	0.560
HGS	KLF4	psi-mi:“MI:0915”(physical association)	0.560
KLF4	GYS1	psi-mi:“MI:0915”(physical association)	0.560
KLF4	HSF2BP	psi-mi:“MI:0915”(physical association)	0.560
KLF4	TLE5	psi-mi:“MI:0915”(physical association)	0.560
MYO15B	KLF4	psi-mi:“MI:0915”(physical association)	0.560
KLF4	PAX9	psi-mi:“MI:0915”(physical association)	0.560
KLF4		psi-mi:“MI:0407”(direct interaction)	0.540
KLF4		psi-mi:“MI:0915”(physical association)	0.540
KDM6A	KLF4	psi-mi:“MI:0915”(physical association)	0.540
CTBP1	KLF4	psi-mi:“MI:0915”(physical association)	0.520
KLF4	CTBP1	psi-mi:“MI:0915”(physical association)	0.520
MBD3	KLF4	psi-mi:“MI:0914”(association)	0.500
MBD3	KLF4	psi-mi:“MI:0915”(physical association)	0.500
AR	KLF4	psi-mi:“MI:0915”(physical association)	0.470
YAP1	KLF4	psi-mi:“MI:0407”(direct interaction)	0.440
KLF4	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
KLF4	KDM6B	psi-mi:“MI:0915”(physical association)	0.400
	KLF4	psi-mi:“MI:0915”(physical association)	0.370
CCL1	KLF4	psi-mi:“MI:0915”(physical association)	0.370
CXCL3	KLF4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (227): KLF4 (Co-localization), KLF4 (Co-localization), CDH1 (Affinity Capture-Western), KLF4 (Affinity Capture-Western), KLF4 (Affinity Capture-MS), KLF4 (Affinity Capture-MS), KLF4 (Affinity Capture-MS), KLF4 (Affinity Capture-MS), KLF4 (Affinity Capture-MS), KLF4 (Affinity Capture-MS), FBXO22 (Affinity Capture-MS), CUL1 (Affinity Capture-MS), SKP1 (Affinity Capture-MS), FBXO22 (Affinity Capture-Western), KLF4 (Affinity Capture-Western)

ESM2 similar proteins: A1XSY8, O08656, O43474, P08046, P08151, P08152, P08154, P09022, P09027, P10070, P11161, P13360, P15976, P17679, P18146, P19544, P22561, P26632, P26633, P31249, P40656, P43300, P43301, P43429, P46153, P47806, P49639, P49952, P50476, P51774, Q05159, Q06889, Q07424, Q08427, Q0VGT2, Q29W20, Q60793, Q61169, Q6NW96, Q6P0J3

Diamond homologs: O08584, O08876, O14901, O35738, O35819, O43474, O62259, O70494, O75840, O89090, O89091, O95600, P08047, P0CG40, P46099, P57682, P58334, Q01714, Q02446, Q02447, Q0VA40, Q13118, Q13351, Q13887, Q14V87, Q19A40, Q19A41, Q22678, Q24266, Q3SY56, Q5XGT8, Q60793, Q60843, Q60980, Q62445, Q64HY3, Q64HY5, Q65ZG6, Q6BEB4, Q6NW96

SIGNOR signaling

23 interactions.

A	Effect	B	Mechanism
KLF4	down-regulates	MYOCD
KLF4	down-regulates	SRF	binding
MRTFA	down-regulates	KLF4
MYOCD	down-regulates	KLF4
STAT6	“up-regulates quantity by expression”	KLF4	“transcriptional regulation”
KLF4	up-regulates	STAT6
KLF4	“down-regulates quantity by repression”	TNF	“transcriptional regulation”
KLF4	“down-regulates quantity by repression”	SOD1	“transcriptional regulation”
KLF4	“up-regulates activity”	THBD	“transcriptional regulation”
MAPK7	“up-regulates quantity by expression”	KLF4	“transcriptional regulation”
KLF4	“up-regulates quantity by expression”	NPNT	“transcriptional regulation”
KLF4	“up-regulates activity”	PBX1	binding
KLF4	“up-regulates activity”	MEIS2	binding
FBXO22	“down-regulates quantity by destabilization”	KLF4	ubiquitination
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	KLF4	ubiquitination
PLK1	“up-regulates quantity by stabilization”	KLF4	phosphorylation
TRAF6	“up-regulates quantity by stabilization”	KLF4	ubiquitination
HUWE1	“down-regulates quantity by destabilization”	KLF4	ubiquitination
CTNNB1	“up-regulates activity”	KLF4	binding
KLF4	“up-regulates quantity by expression”	HSPA8	“transcriptional regulation”
MUC1	“up-regulates activity”	KLF4	binding
KLF4	“down-regulates quantity by repression”	TP53	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PIP3 activates AKT signaling	5	10.1×	9e-03
Ub-specific processing proteases	6	9.7×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	40.4×	5e-05
heart development	5	10.9×	6e-03
chromatin remodeling	5	10.1×	7e-03
protein stabilization	5	9.3×	9e-03
negative regulation of cell population proliferation	7	8.2×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — ALL, BRCA, HCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	11
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

565 predictions. Top by Δscore:

Variant	Effect	Δscore
9:107485922:CTCAC:C	acceptor_gain	1.0000
9:107485923:TCAC:T	acceptor_gain	1.0000
9:107485924:CAC:C	acceptor_gain	1.0000
9:107485924:CACC:C	acceptor_gain	1.0000
9:107485925:AC:A	acceptor_gain	1.0000
9:107485926:CC:C	acceptor_gain	1.0000
9:107485926:CCTG:C	acceptor_loss	1.0000
9:107485927:C:CC	acceptor_gain	1.0000
9:107485935:G:GC	acceptor_gain	1.0000
9:107487022:CCCTA:C	donor_loss	1.0000
9:107487023:CCTAC:C	donor_loss	1.0000
9:107487024:CTAC:C	donor_loss	1.0000
9:107487025:TAC:T	donor_loss	1.0000
9:107487188:GAGCT:G	acceptor_gain	1.0000
9:107487191:CT:C	acceptor_gain	1.0000
9:107487192:TCTAG:T	acceptor_loss	1.0000
9:107487193:C:CC	acceptor_gain	1.0000
9:107487193:CTAGG:C	acceptor_loss	1.0000
9:107488266:CG:C	acceptor_gain	1.0000
9:107488928:A:AC	donor_gain	1.0000
9:107488929:C:CC	donor_gain	1.0000
9:107485929:G:C	acceptor_gain	0.9900
9:107485929:G:GC	acceptor_gain	0.9900
9:107485935:G:C	acceptor_gain	0.9900
9:107487189:AGCT:A	acceptor_gain	0.9900
9:107487426:T:TA	donor_gain	0.9900
9:107488263:CAGCG:C	acceptor_gain	0.9900
9:107488264:AGCG:A	acceptor_gain	0.9900
9:107488265:GCG:G	acceptor_gain	0.9900
9:107488265:GCGCT:G	acceptor_loss	0.9900

AlphaMissense

3086 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000148821 (9:107485823 G>A,T), RS1000570841 (9:107485641 G>A,T), RS1000595607 (9:107489233 A>C), RS1000624697 (9:107490349 C>T), RS1000667310 (9:107490016 G>A), RS1001149035 (9:107486735 T>A), RS1002159049 (9:107486291 C>G), RS1002515109 (9:107486606 G>A), RS1003771888 (9:107487838 T>G), RS1004227052 (9:107491482 G>C), RS1004401105 (9:107487824 G>A), RS1004444441 (9:107487420 A>G), RS1004510522 (9:107490549 A>T), RS1004562756 (9:107490339 G>C), RS1004731741 (9:107486713 G>A)

Disease associations

OMIM: gene MIM:602253 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary palmoplantar keratoderma	Strong	Autosomal dominant
epidermal disease	Moderate	Autosomal dominant

Mondo (2): epidermal disease (MONDO:0019268), hereditary palmoplantar keratoderma (MONDO:0019272)

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000952_9	Breast cancer	2.000000e-10
GCST001702_2	Prostate cancer	5.000000e-14
GCST002652_8	Cotinine glucuronidation	2.000000e-08
GCST002738_20	Psoriasis	3.000000e-06
GCST003061_12	Cutaneous malignant melanoma	6.000000e-07
GCST003061_4	Cutaneous malignant melanoma	7.000000e-11
GCST003208_1	Colorectal or endometrial cancer	8.000000e-06
GCST003268_6	Psoriasis vulgaris	3.000000e-06
GCST005527_29	Psoriasis	2.000000e-08
GCST006073_17	Tenofovir clearance in HIV infection	9.000000e-06
GCST006288_302	Heel bone mineral density	5.000000e-07
GCST006288_484	Heel bone mineral density	6.000000e-08
GCST006288_620	Heel bone mineral density	2.000000e-14
GCST006575_18	Takayasu arteritis	3.000000e-06
GCST006979_166	Heel bone mineral density	2.000000e-10
GCST006979_167	Heel bone mineral density	3.000000e-28
GCST007953_7	Glycated hemoglobin levels	1.000000e-07
GCST007954_23	Glycated hemoglobin levels	2.000000e-07
GCST010396_221	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-06
GCST010866_137	Coronary artery disease	1.000000e-13
GCST011365_73	Myocardial infarction	1.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006508	cotinine glucuronidation measurement
EFO:0004230	endometrial neoplasm
EFO:1001494	psoriasis vulgaris
EFO:0009270	heel bone mineral density
EFO:0004541	HbA1c measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2236599	KLF4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	8
sodium arsenite	affects cotreatment, increases expression, increases reaction, decreases expression, increases abundance	7
Estradiol	affects cotreatment, decreases expression, increases expression, increases reaction	5
Cisplatin	decreases expression, increases expression, affects reaction, decreases reaction, decreases response to substance (+1 more)	4
Tetrachlorodibenzodioxin	decreases expression, increases expression, affects cotreatment	4
Cyclosporine	affects cotreatment, affects expression, increases expression	4
Arsenic Trioxide	affects cotreatment, decreases expression, increases expression, increases reaction, affects reaction (+1 more)	3
Benzo(a)pyrene	increases reaction, increases abundance, increases expression, affects cotreatment	3
Ethinyl Estradiol	affects expression, increases expression	3
Fluorouracil	increases expression, decreases response to substance	3
Oxygen	affects reaction, increases expression, decreases expression	3
Tretinoin	affects cotreatment, decreases expression, increases expression	3
napabucasin	decreases expression	2
bisphenol A	affects cotreatment, increases expression, affects expression	2
methylselenic acid	affects reaction, decreases expression, increases expression, affects expression, increases activity	2
potassium chromate(VI)	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
Chlorpromazine	affects cotreatment, affects expression, decreases expression	2
Formaldehyde	increases expression	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Genistein	decreases expression, increases expression, affects expression, affects cotreatment	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
XMU-MP-1	decreases expression, decreases reaction	1
ethylbenzene	affects cotreatment, decreases expression, increases methylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	affects expression, affects localization	1

Cellosaurus cell lines

16 cell lines: 9 transformed cell line, 4 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3Q8	SEES3-1V human KLF4, clone1	Embryonic stem cell	Male
CVCL_A3Q9	SEES3-1V human KLF4, clone2	Embryonic stem cell	Male
CVCL_A3R0	SEES3-1V human KLF4, clone3	Embryonic stem cell	Male
CVCL_B7TU	e-hChon-1	Transformed cell line	Female
CVCL_B7TV	e-hChon-2	Transformed cell line	Female
CVCL_B7U4	e-hLEC-1	Transformed cell line
CVCL_B7UM	e-hUVEC-5	Transformed cell line
CVCL_B7UT	e-mHepA	Transformed cell line
CVCL_B7UV	e-mHepC	Transformed cell line
CVCL_B8JC	Abcam HCT 116 KLF4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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