KLF14

Summary

KLF14 (KLF transcription factor 14, HGNC:23025) is a protein-coding gene on chromosome 7q32.2, encoding Krueppel-like factor 14 (Q8TD94).

This intronless gene encodes a member of the Kruppel-like family of transcription factors. The encoded protein functions as a transcriptional co-repressor, and is induced by transforming growth factor-beta (TGF-beta) to repress TGF-beta receptor II gene expression. This gene exhibits imprinted expression from the maternal allele in embryonic and extra-embryonic tissues.

Source: NCBI Gene 136259 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 62 total
• MANE Select transcript: NM_138693

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23025
Approved symbol	KLF14
Name	KLF transcription factor 14
Location	7q32.2
Locus type	gene with protein product
Status	Approved
Aliases	BTEB5
Ensembl gene	ENSG00000266265
Ensembl biotype	protein_coding
OMIM	609393
Entrez	136259

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000583337

RefSeq mRNA: 1 — MANE Select: NM_138693 NM_138693

CCDS: CCDS5825

Canonical transcript exons

ENST00000583337 — 1 exons

Exon	Start	End
ENSE00002722754	130730697	130734207

Expression profiles

Bgee: expression breadth broad, 60 present calls, max score 83.87.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.97	gold quality
right adrenal gland cortex	UBERON:0035827	61.68	gold quality
left adrenal gland	UBERON:0001234	61.61	gold quality
right adrenal gland	UBERON:0001233	61.29	gold quality
left adrenal gland cortex	UBERON:0035825	60.72	gold quality
lateral nuclear group of thalamus	UBERON:0002736	60.61	gold quality
cartilage tissue	UBERON:0002418	59.60	gold quality
adrenal cortex	UBERON:0001235	59.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	58.82	gold quality
adrenal gland	UBERON:0002369	57.75	gold quality
gastrocnemius	UBERON:0001388	56.92	gold quality
muscle of leg	UBERON:0001383	56.34	gold quality
heart right ventricle	UBERON:0002080	56.11	gold quality
endothelial cell	CL:0000115	55.97	gold quality
nasal cavity epithelium	UBERON:0005384	55.24	gold quality
lateral globus pallidus	UBERON:0002476	54.82	gold quality
mucosa of paranasal sinus	UBERON:0005030	53.75	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	53.47	gold quality
parotid gland	UBERON:0001831	52.64	gold quality
substantia nigra pars compacta	UBERON:0001965	52.05	gold quality
cerebellar vermis	UBERON:0004720	51.70	gold quality
omental fat pad	UBERON:0010414	51.03	gold quality
peritoneum	UBERON:0002358	51.00	gold quality
subcutaneous adipose tissue	UBERON:0002190	50.69	gold quality
cardia of stomach	UBERON:0001162	50.65	gold quality
adipose tissue of abdominal region	UBERON:0007808	50.53	gold quality
substantia nigra pars reticulata	UBERON:0001966	50.02	gold quality
quadriceps femoris	UBERON:0001377	49.65	gold quality
skeletal muscle tissue	UBERON:0001134	49.48	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
FGFR1
FOXP3
NOTCH1
SPHK1	Activation
TGFBR2	Repression

JASPAR motifs

Motif	Name	Family
MA0740.1	KLF14	Three-zinc finger Kruppel-related
MA0740.2	KLF14	Three-zinc finger Kruppel-related

JASPAR matrix evidence (PMIDs): PMID:16266294

miRNA regulators (miRDB)

32 targeting KLF14, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-4638-3P	97.90	65.75	905
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-346	97.01	66.97	662
HSA-MIR-514A-5P	96.94	65.49	801
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-3690	96.44	65.18	737
HSA-MIR-4522	95.76	66.23	742

Literature-anchored findings (GeneRIF, showing 32)

• KLF14 gene is imprinted, with preferential expression from the maternal allele. (PMID:17480121)
• the TGFbeta pathway activation leads to recruitment of a KLF14-mSin3A-HDAC2 repressor complex to the TGFbetaRII promoter, as well as the remodeling of chromatin to increase histone marks that associate with transcriptional silencing. (PMID:19088080)
• we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression (PMID:21572415)
• The objective of the present study was to detect the association of the rs4731702 single nucleotide polymorphism (SNP) and serum lipid levels in the Guangxi Mulao and Han populations. (PMID:24195066)
• The risk allele C of rs151290 in KCNQ1 and risk allele G of rs972283 in KLF14 were both associated with increased risk of T2DM in a global population. (PMID:24486580)
• This is the first description of the activity and mechanisms underlying the function of KLF14 as an activator protein and novel regulator of lipid signaling. (PMID:24759103)
• KLF14 plays an important role in increasing glucose uptake and insulin sensitivity by the activation of PI3-kinase/Akt signaling pathway in vitro. (PMID:26226221)
• Transduction of HepG2 cells with human KLF14 showed that KLF14 is a regulator of APOA1 expression. (PMID:26368306)
• KLF14 transcription is significantly downregulated, whereas Plk4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and Plk4 protein expression in human breast and colon cancers. (PMID:26439168)
• SNPs at the CETP, HNF4A and KLF14 locus are associated with HDL-C levels and type 2 diabetes (in female participants). (PMID:26670163)
• The modified methylation of TRIM59 and KLF14 in top athletes may be accounted for by the biological roles played by these genes. Their known anti-tumour and anti-inflammatory activities suggests that intense physical training has a complex influence on aging and potentially launches signalling networks that contribute to the observed lower risk of elite athletes to develop cardiovascular disease and cancer. (PMID:29466246)
• Carriers of the KLF14 type 2 diabetes (T2D) risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and these effects on fat distribution, and the T2D association, are female specific. (PMID:29632379)
• T2D risk alleles are cis-eQTLs for KLF14, conferring reduced expression in human adipose tissue. (PMID:29632379)
• The study demonstrated that HAND2-AS1 exerts a suppressive role in colorectal cancer by sponging miR-1275 and modulating KLF14 expression. (PMID:30078677)
• we proved that DGCR5 can rescue the inhibited levels of KLF14 repressed by miR-346 mimics in MHCC-97H and Hep3B cells. Taken together, it was indicated in our study that DGCR5 can restrain the progression of HCC through sponging miR-346 and modulating KLF14 in vitro. (PMID:30216442)
• KIF14 was upregulated in colorectal cancer (CRC) tissues and promoted tumor cell proliferation. Study is the first to comprehensively demonstrate the expression profile and functional roles of KIF14 in CRC and reveal that downregulated miR-200c expression may contribute to increased KIF14 expression. (PMID:30226594)
• KLF14 inhibits the inflammatory response in endothelial cells; its protective effects are mediated by transcriptional inhibition of NF-kappaB p65 (PMID:30248551)
• downregulated in chronic liver diseases (PMID:30254317)
• These results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for castration-resistant prostate cancer treatment. (PMID:30400002)
• Epstein-Barr Virus Facilitates Expression of KLF14 by Regulating the Cooperative Binding of the E2F-Rb-HDAC Complex in Latent Infection. (PMID:32847849)
• The KLF14 Variant is Associated with Type 2 Diabetes and HbA1C Level. (PMID:33389382)
• Kruppel-like factor 14 deletion in myeloid cells accelerates atherosclerotic lesion development. (PMID:33538785)
• EZH2-mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPARgamma. (PMID:34031939)
• Differential Genetic and Epigenetic Effects of the KLF14 Gene on Body Shape Indices and Metabolic Traits. (PMID:35456983)
• Determining KLF14 tertiary structure and diagnostic significance in brain cancer progression. (PMID:35577881)
• Upregulation of KLF14 expression attenuates kidney fibrosis by inducing PPARalpha-mediated fatty acid oxidation. (PMID:36584797)
• KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2. (PMID:36600258)
• KLF14/miR-1283/TFAP2C axis inhibits HER2-positive breast cancer progression via declining tumor cell proliferation. (PMID:36752341)
• Biochemical association of regulatory variant of KLF14 genotype in the pathogenesis of cardiodiabetic patients. (PMID:37351102)
• Potential Association of The Pathogenic Kruppel-like Factor 14 (KLF14) and Adiponectin (ADIPOQ) SNVs with Susceptibility to T2DM. (PMID:38031795)
• KLF14 activates the JNK-signaling pathway to induce S-phase arrest in cervical cancer cells. (PMID:38143751)
• KLF14 directly downregulates the expression of GPX4 to exert antitumor effects by promoting ferroptosis in cervical cancer. (PMID:39390559)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	klf1	ENSDARG00000017400
danio_rerio	klf5l	ENSDARG00000018757
danio_rerio	klf17	ENSDARG00000038792
danio_rerio	klf13	ENSDARG00000061368
danio_rerio	zgc:153115	ENSDARG00000069342
danio_rerio	si:ch211-117k10.3	ENSDARG00000090914
danio_rerio	sp5l	ENSDARG00000115868
mus_musculus	Klf14	ENSMUSG00000073209
rattus_norvegicus	Klf14	ENSRNOG00000027557
drosophila_melanogaster	Klf15	FBGN0025679
drosophila_melanogaster	CG3065	FBGN0034946
drosophila_melanogaster	luna	FBGN0040765
drosophila_melanogaster	CG42741	FBGN0261705
drosophila_melanogaster	dar1	FBGN0263239
caenorhabditis_elegans		WBGENE00018990

Paralogs (22): KLF6 (ENSG00000067082), KLF8 (ENSG00000102349), KLF5 (ENSG00000102554), KLF1 (ENSG00000105610), KLF3 (ENSG00000109787), KLF7 (ENSG00000118263), KLF12 (ENSG00000118922), KLF9 (ENSG00000119138), KLF2 (ENSG00000127528), KLF16 (ENSG00000129911), KLF4 (ENSG00000136826), KLF10 (ENSG00000155090), KLF15 (ENSG00000163884), SP8 (ENSG00000164651), KLF13 (ENSG00000169926), SP7 (ENSG00000170374), KLF17 (ENSG00000171872), KLF11 (ENSG00000172059), SP6 (ENSG00000189120), SP5 (ENSG00000204335), SP9 (ENSG00000217236), KLF18 (ENSG00000283039)

Protein

Protein identifiers

Krueppel-like factor 14 — Q8TD94 (reviewed: Q8TD94)

Alternative names: Basic transcription element-binding protein 5, Transcription factor BTEB5

All UniProt accessions (1): Q8TD94

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus.

Similarity. Belongs to the Sp1 C2H2-type zinc-finger protein family.

RefSeq proteins (1): NP_619638* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096

UniProt features (17 total): region of interest 5, compositionally biased region 4, zinc finger region 3, sequence conflict 3, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TD94-F1	58.35	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 90 (showing top): PAX4_01, SP3_Q3, GOBP_SPHINGOLIPID_MEDIATED_SIGNALING_PATHWAY, HNF1_Q6, LHX3_01, NKX61_01, EVI1_05, CDP_01, chr7q32, WTGAAAT_UNKNOWN, TGIF_01, RYTAAWNNNTGAY_UNKNOWN, TGACATY_UNKNOWN, HTF_01, IRF_Q6

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of sphingolipid mediated signaling pathway (GO:1902070)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), chromatin binding (GO:0003682), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), metal ion binding (GO:0046872)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
positive regulation of DNA-templated transcription	1
positive regulation of signal transduction	1
sphingolipid mediated signaling pathway	1
regulation of sphingolipid mediated signaling pathway	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
binding	1
transition metal ion binding	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLF14	ELOVL2	Q9NXB9	668
KLF14	TRIM59	Q8IWR1	620
KLF14	ELOVL5	Q9NYP7	612
KLF14	FHL2	Q14192	600
KLF14	SIN3A	Q96ST3	589
KLF14	CDKAL1	Q5VV42	575
KLF14	ARAP1	Q96P48	573
KLF14	MTNR1B	P49286	571
KLF14	ZFAND6	Q6FIF0	570
KLF14	ZBED3	Q96IU2	545
KLF14	C5orf67	F2Z3F1	542
KLF14	KCNQ1	P51787	525
KLF14	JAZF1	Q86VZ6	511
KLF14	TCF7L2	Q9NQB0	508
KLF14	SLC30A8	Q8IWU4	506

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1B0GUA5, A0A286YF58, A0A494C0N9, A0A494C0Y3, A0A7I2V3R4, A0JNN8, A2ARS0, A2VDX9, A5PJP1, A6NGB7, A8MVW0, C9JTQ0, O14511, O14559, O35392, O35569, O43541, O60548, O70220, P0DPE3, Q08102, Q14V87, Q19A40, Q29RK8, Q2HJ59, Q3TYP4, Q5BLP8, Q5T442, Q63244, Q6F5E0, Q6QNY0, Q6VUP9, Q80WY3, Q80XF7, Q8BQU6, Q8K025, Q8K071, Q8TD94, Q8WY41, Q8WZ71

Diamond homologs: A1C6L9, A1DH89, A2QCJ9, B0XSK6, B8NGC8, G4N3L5, K9GKQ6, O14335, O74252, O94166, P08047, P0CG40, P10069, P13574, P27705, P43079, P46099, P58334, P78871, Q01981, Q05620, Q08400, Q0VA40, Q13351, Q14V87, Q19A40, Q22678, Q24266, Q3SY56, Q4WRE4, Q4X0Z3, Q5AMH6, Q5XGT8, Q62511, Q64HY3, Q64HY5, Q6BEB4, Q6NW96, Q6P0J3, Q8BMJ8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KLF14	“up-regulates quantity by expression”	SPHK1	“transcriptional regulation”
KLF14	“down-regulates quantity by repression”	TGFBR2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2053 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:130733215:A:C	H273Q	1.000
7:130733215:A:T	H273Q	1.000
7:130733242:G:C	F264L	1.000
7:130733242:G:T	F264L	1.000
7:130733243:A:C	F264C	1.000
7:130733243:A:G	F264S	1.000
7:130733244:A:G	F264L	1.000
7:130733255:C:G	C260S	1.000
7:130733256:A:G	C260R	1.000
7:130733256:A:T	C260S	1.000
7:130733265:A:G	C257R	1.000
7:130733269:G:C	F255L	1.000
7:130733269:G:T	F255L	1.000
7:130733271:A:G	F255L	1.000
7:130733287:G:C	H249Q	1.000
7:130733287:G:T	H249Q	1.000
7:130733289:G:C	H249D	1.000
7:130733299:G:C	H245Q	1.000
7:130733299:G:T	H245Q	1.000
7:130733301:G:C	H245D	1.000
7:130733301:G:T	H245N	1.000
7:130733326:A:C	F236L	1.000
7:130733326:A:T	F236L	1.000
7:130733327:A:C	F236C	1.000
7:130733327:A:G	F236S	1.000
7:130733328:A:G	F236L	1.000
7:130733339:C:G	C232S	1.000
7:130733339:C:T	C232Y	1.000
7:130733340:A:G	C232R	1.000
7:130733340:A:T	C232S	1.000

dbSNP variants (sampled 300 via entrez): RS1000410525 (7:130735157 C>A,T), RS1003178540 (7:130731659 G>A), RS1003293097 (7:130731393 A>G), RS1004460714 (7:130731586 G>A,C), RS1004896023 (7:130731312 C>A,G,T), RS1005938779 (7:130732182 T>C), RS1006162693 (7:130732395 A>G,T), RS1006546357 (7:130732725 T>C), RS1006778615 (7:130735949 C>T), RS1008253620 (7:130733686 G>A,T), RS1008288682 (7:130730797 G>T), RS1008318089 (7:130730366 C>T), RS1009337121 (7:130735626 G>T), RS1010022855 (7:130735555 C>A,T), RS1012068658 (7:130730309 G>C)

Disease associations

OMIM: gene MIM:609393 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ferrous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3P3	SEES3-1V human KLF14, clone1	Embryonic stem cell	Male
CVCL_A3P4	SEES3-1V human KLF14, clone2	Embryonic stem cell	Male
CVCL_A3P5	SEES3-1V human KLF14, clone3	Embryonic stem cell	Male
CVCL_D8ER	Ubigene BEL-7402 KLF14 KO	Cancer cell line	Female
CVCL_XV69	HEK293 eGFP-KLF14	Transformed cell line	Female

Clinical trials (associated diseases)

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