KLF1

Summary

KLF1 (KLF transcription factor 1, HGNC:6345) is a protein-coding gene on chromosome 19p13.13, encoding Krueppel-like factor 1 (Q13351). Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis.

This gene encodes a hematopoietic-specific transcription factor that induces high-level expression of adult beta-globin and other erythroid genes. The zinc-finger protein binds to the DNA sequence CCACACCCT found in the beta hemoglobin promoter. Heterozygous loss-of-function mutations in this gene result in the dominant In(Lu) blood phenotype.

Source: NCBI Gene 10661 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital dyserythropoietic anemia type 4 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 226 total — 14 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 69
• Druggable target: yes
• Transcription factor: yes — 34 downstream targets (CollecTRI)
• MANE Select transcript: NM_006563

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6345
Approved symbol	KLF1
Name	KLF transcription factor 1
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	EKLF
Ensembl gene	ENSG00000105610
Ensembl biotype	protein_coding
OMIM	600599
Entrez	10661

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000264834, ENST00000876185

RefSeq mRNA: 1 — MANE Select: NM_006563 NM_006563

CCDS: CCDS12285

Canonical transcript exons

ENST00000264834 — 3 exons

Exon	Start	End
ENSE00000682687	12885317	12886142
ENSE00001128698	12887054	12887201
ENSE00001311300	12884422	12885060

Expression profiles

Bgee: expression breadth broad, 86 present calls, max score 93.62.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.8459 / max 840.1294, expressed in 109 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179417	5.8459	109

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	93.62	gold quality
bone marrow	UBERON:0002371	87.90	gold quality
blood	UBERON:0000178	83.92	gold quality
bone marrow cell	CL:0002092	82.77	gold quality
monocyte	CL:0000576	73.21	gold quality
mononuclear cell	CL:0000842	72.94	gold quality
leukocyte	CL:0000738	72.00	gold quality
endometrium epithelium	UBERON:0004811	63.77	gold quality
frontal pole	UBERON:0002795	62.19	gold quality
middle frontal gyrus	UBERON:0002702	62.14	gold quality
paraflocculus	UBERON:0005351	61.77	gold quality
tibialis anterior	UBERON:0001385	58.45	silver quality
granulocyte	CL:0000094	58.06	gold quality
epithelial cell of pancreas	CL:0000083	57.98	gold quality
ventricular zone	UBERON:0003053	56.57	gold quality
decidua	UBERON:0002450	56.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	56.39	gold quality
deltoid	UBERON:0001476	54.70	silver quality
ileal mucosa	UBERON:0000331	54.42	silver quality
biceps brachii	UBERON:0001507	54.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	53.91	gold quality
spleen	UBERON:0002106	53.83	gold quality
pancreatic ductal cell	CL:0002079	53.65	silver quality
ganglionic eminence	UBERON:0004023	53.65	gold quality
upper leg skin	UBERON:0004262	53.31	gold quality
amniotic fluid	UBERON:0000173	53.03	silver quality
hair follicle	UBERON:0002073	52.43	gold quality
quadriceps femoris	UBERON:0001377	52.29	gold quality
thymus	UBERON:0002370	51.73	gold quality
vastus lateralis	UBERON:0001379	51.53	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	1080.03
E-MTAB-7407	yes	544.67
E-ANND-5	yes	530.51
E-MTAB-8271	yes	522.74
E-CURD-112	yes	517.17
E-MTAB-9067	yes	382.86
E-MTAB-8884	yes	315.92
E-HCAD-6	yes	241.55
E-HCAD-4	yes	160.45
E-MTAB-10042	yes	45.01
E-CURD-122	yes	22.32
E-MTAB-9221	yes	13.43
E-ANND-3	yes	10.34
E-HCAD-9	yes	9.40
E-MTAB-9388	yes	9.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

34 targets.

Target	Regulation
ADAM2
AHSP
ANK2	Unknown
BCL11A	Activation
CDKN1A
CDKN1B
CDKN2C	Activation
CEL
DNASE1
DNASE2
E2F2	Unknown
FLI1
FTMT
GP9
GYPB
HBA2
HBB	Unknown
HBD
HBE1
HBG1	Unknown
HBG2
IL12B	Unknown
KAT2B
KLF1
KLF3
KLF8	Activation
NOTCH1
PIAS1
PRMT1
SLC4A1	Unknown

JASPAR motifs

Motif	Name	Family
MA0493.2	KLF1	Three-zinc finger Kruppel-related
MA0493.3	KLF1	Three-zinc finger Kruppel-related

JASPAR matrix evidence (PMIDs): PMID:7682653

Upstream regulators (CollecTRI, top): FLI1, GATA1, GATA2, KLF1, MYB, MYC, SMAD5, SMAD6, SMARCC1, SMARCC2

miRNA regulators (miRDB)

27 targeting KLF1, 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-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6876-3P	98.97	65.69	765
HSA-MIR-626	98.89	66.21	762
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-4475	97.36	66.95	761
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-3192-5P	96.98	65.76	1926
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-1292-5P	96.74	62.14	238
HSA-MIR-644A	96.02	66.52	786
HSA-MIR-1468-5P	94.18	69.04	176
HSA-MIR-1298-3P	94.05	64.84	620
HSA-MIR-3677-3P	93.96	67.89	56

Literature-anchored findings (GeneRIF, showing 40)

• nuclear localization determinants of EKLF depend on basic residues with the Kruppel zinc finter dna binding domains (PMID:11844803)
• bifunctional control of IL-12 p40 by EKLF and its modulation of NFkappaB support a potential function for this factor in orchestrating IL-12 p40 production in macrophages (PMID:14976188)
• Erythroid Kruppel-like factor (EKLF; KLF1) is a transcription factor, originally identified in this laboratory, which plays a crucial role as a transcriptional activator at the adult beta-globin locus. (PMID:16184297)
• Our results further indicate that in hematopoietic progenitors, EKLF influences chromatin organization at the human beta-globin locus and is instrumental for human beta-gene potentiation (PMID:16858401)
• Sp1/Sp3, but not EKLF, is involved in the activation of the GATA-1 erythroid promoter, and that histones H3 and H4 are highly acetylated in this promoter region for an actively transcribed GATA-1 (PMID:18195733)
• These studies suggest there is an unexplored role for EKLF in the cytoplasm that is separate from its well-characterized nuclear function. (PMID:18329016)
• A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. (PMID:18487511)
• EKLF restricts megakaryocytic differentiation to the benefit of erythrocytic differentiation and suggest that this might be at least partially mediated by the inhibition of FLI-1 recruitment to megakaryocytic and Fli-1 gene promoters. (PMID:18523154)
• A higher expression of EKLF was found in secondary AML versus primary AML. Nevertheless, patients expressing EKLF had a longer overall survival and event free survival than those patients that did not express EKLF. (PMID:19097174)
• EKLF and the co-activator BRG1 are co-opted by short-chain fatty acid derivatives to activate the gamma globin genes (PMID:19220418)
• EKLF directs different modes of tissue-specific transcriptional activation depending on the architecture of its target core promoter. (PMID:19251649)
• The effect of EKLF on megakaryocyte-erythroid progenitor lineage decision and commitment is cell autonomous in bone marrow reconstitution assays where stem cells lacking EKLF favor the megakaryocyte differentiation pathway. (PMID:19850899)
• Results indicate that detailed analysis of the distribution of the HBB gene mutations is useful for genetic counseling in the region. (PMID:20642331)
• KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. (PMID:20676097)
• Haploinsufficiency for KLF1 causes hereditary persistence of fetal hemoglobin. (PMID:20676099)
• Overexpression of either KLF1 or LMO2 partially rescued the defect in erythropoiesis caused by c-myb silencing, whereas only KLF1 was also able to repress the megakaryocyte differentiation enhanced in Myb-silenced CD34+ cells. (PMID:20686118)
• the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans. (PMID:21055716)
• KLF1, a vital erythroid transcription factor, activates BCL11A and assists in coordinating the switch from fetal to adult hemoglobin (PMID:21157349)
• KLF1 Directly Coordinates Almost All Aspects of Terminal Erythroid Differentiation. (PMID:21190291)
• Data show that the association of KLF1 mutations with very high levels of zinc protoporphyrin. (PMID:21273267)
• KLF1 and KLF2 positively regulate the embryonic and fetal beta-globin genes through direct promoter binding. (PMID:21610079)
• solution structure of the EKLFTAD2/Tfb1PH complex indicates that EKLFTAD2 binds Tfb1PH in an extended conformation, which is in contrast to the alpha-helical conformation seen for p53TAD2 in complex with Tfb1PH (PMID:21670263)
• E325K protein may therefore actively interfere with EKLF-dependent processes by destabilizing transcription complexes, providing a rational explanation for the severity of the disease phenotype. (PMID:21778342)
• Six different KLF1 mutations were identified in 52 of 145 subjects with borderline HBA2 and normal mean corpuscular volume and mean corpuscular hemoglobin. (PMID:21821711)
• Mutated KLF1 results in delayed fetal hemoglobin switching in humans, confirming previous in vitro and animal studies and the crucial role of KLF1 in regulating globin gene expression. (PMID:22093801)
• KLF1 mutations could make a significant contribution to Hb F variance in malarial regions where hemogobinopathies are common. A single altered KLF1 allele is sufficient to increase Hb F levels. (PMID:22102705)
• Studies show that Ppm1b plays a multilayered role in regulating the availability and optimal activity of the EKLF protein in erythroid cells. (PMID:22393050)
• EKLF mRNA level was significantly decreased in the blood and bone marrow of 5q- syndrome and in all Diamond-Blackfan anemia patients. (PMID:22965552)
• Data show that KLF1 haploinsufficiency is responsible for the In(Lu) blood type. (PMID:23125034)
• The 1st KLF1 gene promoter mutation (KLF1:g.-148G > A) associated with increased HbF resides in an Sp1 binding site & prevents Sp1 binding. It is involved in human fetal globin gene switching. (PMID:23161389)
• Regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction (PMID:23209159)
• Simvastatin and tBHQ suppress KLF1 and BCL11 gene expression and additively increase fetal hemoglobin in primary human erythroid cells. (PMID:23223429)
• KLF1 conscripts the adult-stage beta-globin gene to replace the gamma-globin gene within the active chromatin hub in a stage-specific manner. (PMID:23474875)
• Data suggest that the Kruppel-like factor 1 (KLF) mutations could be one of the causes of hereditary persistence of fetal hemoglobin (HPFH) in regions where thalassemias are common. (PMID:23806141)
• Select activation-degradation regions like the ones found in EKLF and SREBP1a function in part through their ability to form noncovalent interactions with ubiquitin. (PMID:24139988)
• Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. (PMID:24443441)
• In erythroid cells, pull down experiments identified the presence of a novel complex formed by HDAC5, GATA1, EKLF and pERK which was instead undetectable in cells of the megakaryocytic lineage. (PMID:24594363)
• The frequency of rare Lu(a-b-) blood group in Shanghai was approximately 0.02%, and all the individuals had an In(Lu) phenotype. The molecular basis of such samples may be related to mutations in the EKLF/KLF1 gene. (PMID:24711040)
• findings suggest that KLF1 mutations occur selectively in the presence of beta-thalassemia to increase the production of HbF, which in turn ameliorates the clinical severity of beta-thalassemia. (PMID:24829204)
• Molecular defect in the alpha-globin and beta-globin genes, and in the KLF1 gene were found in the borderline hemoglobin A2 Chinese individuals. (PMID:24857170)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Klf1	ENSMUSG00000054191
rattus_norvegicus	Klf1	ENSRNOG00000003443
drosophila_melanogaster	luna	FBGN0040765

Paralogs (22): KLF6 (ENSG00000067082), KLF8 (ENSG00000102349), KLF5 (ENSG00000102554), 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), KLF14 (ENSG00000266265), KLF18 (ENSG00000283039)

Protein

Protein identifiers

Krueppel-like factor 1 — Q13351 (reviewed: Q13351)

Alternative names: Erythroid krueppel-like transcription factor

All UniProt accessions (1): Q13351

UniProt curated annotations — full annotation on UniProt →

Function. Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis. Is a dual regulator of fetal-to-adult globin switching. Binds to the CACCC box in the beta-globin gene promoter and acts as a preferential activator of this gene. Furthermore, it binds to the BCL11A promoter and activates expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. This dual activity ensures that, in most adults, fetal hemoglobin levels are low. Able to activate CD44 and AQP1 promoters. When sumoylated, acts as a transcriptional repressor by promoting interaction with CDH2/MI2beta and also represses megakaryocytic differentiation.

Subunit / interactions. Interacts with PCAF; the interaction does not acetylate EKLF and inhibits its transactivation activity. Interacts with CREBBP/CBP and EP300; the interactions enhance the transactivation activity. Interacts with TFB1.

Subcellular location. Nucleus.

Tissue specificity. Expression restricted to adult bone marrow and fetal liver. Not expressed in myeloid nor lymphoid cell lines.

Post-translational modifications. Acetylated; can be acetylated on both Lys-274 and Lys-288. Acetylation on Lys-274 (by CBP) appears to be the major site affecting EKLF transactivation activity. Sumoylated; sumoylation, promoted by PIAS1, leads to repression of megakaryocyte differentiation. Also promotes the interaction with the CDH4 subunit of the NuRD repression complex. Phosphorylated primarily on serine residues in the transactivation domain. Phosphorylation on Thr-23 is critical for the transactivation activity.

Disease relevance. Anemia, congenital dyserythropoietic, 4A (CDAN4A) [MIM:613673] An autosomal dominant blood disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals also have increased levels of fetal hemoglobin. The disease is caused by variants affecting the gene represented in this entry. Anemia, congenital dyserythropoietic, 4B (CDAN4B) [MIM:620969] An autosomal recessive hematologic disorder characterized by neonatal jaundice, hyperbilirubinemia, ineffective erythropoiesis in the bone marrow, and severe congenital hemolytic anemia. Fetal and embryonic hemoglobin are increased and persistent. The disease is caused by variants affecting the gene represented in this entry.

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

Polymorphism. Genetic variations in KLF1 underlie the fetal hemoglobin quantitative trait locus 6 (HBFQTL6) [MIM:613566]. Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. In healthy adults, fetal hemoglobin (HbF) is present at residual levels (less than 0.06% of total hemoglobin) with over 20-fold variation. Ten to fifteen percent of adults fall within the upper tail of the distribution. Genetic variations in KLF1 underlie the blood group-Lutheran inhibitor (In(Lu)) phenotype [MIM:111150]; also known as dominant Lu (a-b-) phenotype. In(Lu) is characterized phenotypically by the apparent absence of the Lu antigen (BCAM) on red blood cells during serologic tests: Lu(a-b-).

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

RefSeq proteins (1): NP_006554* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013087	Znf_C2H2_type	Domain
IPR031784	EKLF_TAD2	Domain
IPR031786	EKLF_TAD1	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096, PF16832, PF16833

UniProt features (45 total): sequence variant 24, modified residue 4, sequence conflict 4, zinc finger region 3, region of interest 2, strand 2, compositionally biased region 2, chain 1, cross-link 1, helix 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2L2I	SOLUTION NMR
2MBH	SOLUTION NMR
2N23	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13351-F1	58.11	0.01

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 (5): 184, 274, 288, 54, 23

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 270 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GNF2_PRDX2, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_ERYTHROCYTE_HOMEOSTASIS, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, MARKS_ACETYLATED_NON_HISTONE_PROTEINS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GNF2_ANK1, GOBP_PROTEIN_DESTABILIZATION, MODULE_195, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (8): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), ubiquitin-dependent protein catabolic process (GO:0006511), erythrocyte differentiation (GO:0030218), protein destabilization (GO:0031648), positive regulation of DNA-templated transcription (GO:0045893), maternal process involved in female pregnancy (GO:0060135), cellular response to endothelin (GO:1990859)

GO Molecular Function (9): 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), DNA-binding transcription factor activity (GO:0003700), zinc ion binding (GO:0008270), ubiquitin binding (GO:0043130), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
regulation of protein stability	1
positive regulation of RNA biosynthetic process	1
female pregnancy	1
multicellular organismal reproductive process	1
cellular response to peptide hormone stimulus	1
response to endothelin	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
transition metal ion binding	1
ubiquitin-like protein binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1569 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLF1	GATA1	P15976	986
KLF1	A0A0J9YYA3	A0A0J9YYA3	913
KLF1	TAL1	P17542	901
KLF1	HBB	P02023	885
KLF1	ZFPM1	Q8IX07	875
KLF1	LDB1	Q86U70	869
KLF1	HBE1	P02100	856
KLF1	LDB2	O43679	793
KLF1	LMO2	P25791	787
KLF1	HBA1	P01922	777
KLF1	KAT2B	Q92831	769
KLF1	CDAN1	Q8IWY9	742
KLF1	SEC23B	Q15437	741
KLF1	EPOR	P19235	739
KLF1	SOX6	P35712	733

IntAct

68 interactions, top by confidence:

A	B	Type	Score
KLF1	TFB1	psi-mi:“MI:0407”(direct interaction)	0.560
KLF1	GTF2H1	psi-mi:“MI:0407”(direct interaction)	0.560
KLF1	PATZ1	psi-mi:“MI:0915”(physical association)	0.560
SNRPC	KLF1	psi-mi:“MI:0915”(physical association)	0.560
TIAL1	KLF1	psi-mi:“MI:0915”(physical association)	0.560
KLF1	CCDC57	psi-mi:“MI:0915”(physical association)	0.560
MKRN3	KLF1	psi-mi:“MI:0915”(physical association)	0.560
PRR3	KLF1	psi-mi:“MI:0915”(physical association)	0.560
KLF1	RBM4B	psi-mi:“MI:0915”(physical association)	0.560
KLF1	DVL3	psi-mi:“MI:0915”(physical association)	0.560
EFEMP2	KLF1	psi-mi:“MI:0915”(physical association)	0.560
C1QBP	KLF1	psi-mi:“MI:0915”(physical association)	0.560
GYS1	KLF1	psi-mi:“MI:0915”(physical association)	0.560
KLF1	PCBP1	psi-mi:“MI:0915”(physical association)	0.560
RBM10	KLF1	psi-mi:“MI:0915”(physical association)	0.560
KLF1	RBPMS2	psi-mi:“MI:0915”(physical association)	0.560
TLE5	KLF1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPK	KLF1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPF	KLF1	psi-mi:“MI:0915”(physical association)	0.560
VPS37C	KLF1	psi-mi:“MI:0915”(physical association)	0.560
KLF1	CREBBP	psi-mi:“MI:0407”(direct interaction)	0.440
KLF1	EP300	psi-mi:“MI:0407”(direct interaction)	0.440
KLF1		psi-mi:“MI:0407”(direct interaction)	0.440
UBC	KLF1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440

BioGRID (45): ARID1A (Reconstituted Complex), SMARCA4 (Reconstituted Complex), SMARCC2 (Reconstituted Complex), SMARCC1 (Reconstituted Complex), SMARCD1 (Reconstituted Complex), SMARCE1 (Reconstituted Complex), SMARCB1 (Reconstituted Complex), KLF1 (Biochemical Activity), KLF1 (Biochemical Activity), CSNK2A2 (Reconstituted Complex), CSNK2A1 (Reconstituted Complex), KLF1 (Biochemical Activity), KLF1 (Two-hybrid), KLF1 (Two-hybrid), KLF1 (Two-hybrid)

ESM2 similar proteins: A0A2Z4LIS9, A2CE44, A6NFI3, E9PZZ1, O95201, P09066, P15863, P19622, P22091, P46099, P49640, P70338, P82976, P97503, P98168, P98169, Q05917, Q07120, Q13351, Q14549, Q14V87, Q15270, Q19A40, Q2QGD7, Q3SY56, Q3U133, Q58DK7, Q5DWN0, Q6IQX8, Q6NUN9, Q8C8V1, Q8NCA9, Q8TD94, Q8WUU4, Q924A2, Q92618, Q96RK0, Q99684, Q9BV97, Q9BYN7

Diamond homologs: A5ABV9, O08876, O14901, O70494, O89090, O89091, P08047, P0CG40, P41696, Q01714, Q02446, Q02447, Q0VA40, Q13351, Q22678, Q3SY56, Q5XGT8, Q62445, Q64HY3, Q64HY5, Q6BEB4, Q6NW96, Q6P0J3, Q8BMJ8, Q8IXZ3, Q8K1S5, Q8TDD2, Q8VI67, Q90WR8, Q9ESX2, Q9JHX2, Q9TZ64, A1C6L9, A1DH89, A2QCJ9, B0XSK6, B8NGC8, G4N3L5, K9GKQ6, O14335

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CBP/p300	“up-regulates activity”	KLF1	acetylation
KLF1	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
CREBBP	“up-regulates activity”	KLF1	acetylation
KLF1	up-regulates	Erythrocyte_differentiation
CSNK2A1	“up-regulates activity”	KLF1	phosphorylation
CSNK2A2	“up-regulates activity”	KLF1	phosphorylation
FLI1	“down-regulates activity”	KLF1	binding
KLF1	“down-regulates activity”	FLI1	binding
GATA1	“up-regulates quantity by expression”	KLF1	“transcriptional regulation”
GATA2	“up-regulates quantity by expression”	KLF1	“transcriptional regulation”
KLF1	“up-regulates quantity by expression”	KLF8	“transcriptional regulation”
KLF1	“up-regulates quantity by expression”	CDKN2C	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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
mRNA Polyadenylation	7	36.2×	2e-07
Processing of Capped Intron-Containing Pre-mRNA	6	29.0×	7e-06
mRNA Splicing - Major Pathway	6	19.3×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
mRNA splicing, via spliceosome	5	20.8×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	7
Uncertain significance	123
Likely benign	48
Benign	10

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
2045154	NM_006563.5(KLF1):c.609C>A (p.Tyr203Ter)	Pathogenic
2064376	NM_006563.5(KLF1):c.406del (p.Val136fs)	Pathogenic
3358908	KLF1, -154C-T	Pathogenic
3358910	NM_006563.5(KLF1):c.172C>T (p.Gln58Ter)	Pathogenic
3358912	NM_006563.5(KLF1):c.1012C>A (p.Pro338Thr)	Pathogenic
3611730	NM_006563.5(KLF1):c.765dup (p.Gly256fs)	Pathogenic
40066	NM_006563.5(KLF1):c.1071C>A (p.His357Gln)	Pathogenic
40067	NM_006563.5(KLF1):c.591C>G (p.Tyr197Ter)	Pathogenic
4710513	NM_006563.5(KLF1):c.802C>T (p.Arg268Ter)	Pathogenic
56891	NM_006563.5(KLF1):c.892G>C (p.Ala298Pro)	Pathogenic
56892	NM_006563.5(KLF1):c.1012C>T (p.Pro338Ser)	Pathogenic
9000	NM_006563.5(KLF1):c.569del (p.Pro190fs)	Pathogenic
9001	NM_006563.5(KLF1):c.874A>T (p.Lys292Ter)	Pathogenic
9002	NM_006563.5(KLF1):c.895C>T (p.His299Tyr)	Pathogenic
100796	NM_006563.5(KLF1):c.1001C>G (p.Thr334Arg)	Likely pathogenic
100797	NM_006563.5(KLF1):c.1022G>A (p.Cys341Tyr)	Likely pathogenic
100800	NM_006563.5(KLF1):c.895C>G (p.His299Asp)	Likely pathogenic
100801	NM_006563.5(KLF1):c.913+1G>A	Likely pathogenic
2851757	NM_006563.5(KLF1):c.87+1G>A	Likely pathogenic
3765538	NM_006563.5(KLF1):c.858C>A (p.Cys286Ter)	Likely pathogenic
4542311	NM_006563.5(KLF1):c.89G>A (p.Trp30Ter)	Likely pathogenic

SpliceAI

347 predictions. Top by Δscore:

Variant	Effect	Δscore
19:12887067:T:TA	donor_gain	1.0000
19:12885058:CCC:C	acceptor_gain	0.9900
19:12885059:CCC:C	acceptor_gain	0.9900
19:12885060:CCT:C	acceptor_loss	0.9900
19:12885061:C:CA	acceptor_loss	0.9900
19:12885062:T:A	acceptor_loss	0.9900
19:12886138:CACCA:C	acceptor_gain	0.9900
19:12886140:CCA:C	acceptor_gain	0.9900
19:12886141:CA:C	acceptor_gain	0.9900
19:12886141:CAC:C	acceptor_gain	0.9900
19:12885056:CTCCC:C	acceptor_gain	0.9800
19:12885059:CC:C	acceptor_gain	0.9800
19:12885060:CC:C	acceptor_gain	0.9800
19:12885061:C:CC	acceptor_gain	0.9800
19:12885311:CCTCA:C	donor_loss	0.9800
19:12885312:CTCAC:C	donor_loss	0.9800
19:12885313:TCA:T	donor_loss	0.9800
19:12885314:CA:C	donor_loss	0.9800
19:12885315:ACC:A	donor_loss	0.9800
19:12885316:C:CT	donor_loss	0.9800
19:12885964:C:CT	donor_gain	0.9800
19:12886143:C:CC	acceptor_gain	0.9800
19:12885965:C:CT	donor_gain	0.9700
19:12887049:CCCAC:C	donor_loss	0.9600
19:12887051:CA:C	donor_loss	0.9600
19:12887052:AC:A	donor_loss	0.9600
19:12887053:C:CC	donor_loss	0.9600
19:12887066:AT:A	donor_gain	0.9600
19:12886139:ACCA:A	acceptor_gain	0.9500
19:12886140:CCAC:C	acceptor_gain	0.9500

AlphaMissense

2290 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:12884930:A:C	F348L	1.000
19:12884930:A:T	F348L	1.000
19:12884932:A:G	F348L	1.000
19:12884953:A:G	C341R	1.000
19:12885014:G:C	F320L	1.000
19:12885014:G:T	F320L	1.000
19:12885015:A:G	F320S	1.000
19:12885016:A:G	F320L	1.000
19:12885041:G:C	C311W	1.000
19:12885043:A:G	C311R	1.000
19:12884903:G:C	H357Q	0.999
19:12884903:G:T	H357Q	0.999
19:12884905:G:C	H357D	0.999
19:12884913:A:G	L354P	0.999
19:12884931:A:G	F348S	0.999
19:12884942:G:C	C344W	0.999
19:12884944:A:G	C344R	0.999
19:12884951:G:C	C341W	0.999
19:12884952:C:G	C341S	0.999
19:12884953:A:T	C341S	0.999
19:12884957:G:C	F339L	0.999
19:12884957:G:T	F339L	0.999
19:12884959:A:G	F339L	0.999
19:12884975:G:C	H333Q	0.999
19:12884975:G:T	H333Q	0.999
19:12884977:G:C	H333D	0.999
19:12884982:C:G	R331P	0.999
19:12884987:G:C	H329Q	0.999
19:12884987:G:T	H329Q	0.999
19:12884989:G:C	H329D	0.999

dbSNP variants (sampled 300 via entrez): RS1000761870 (19:12885252 C>A), RS1001134406 (19:12887733 A>G), RS1001397411 (19:12887564 C>T), RS1001756626 (19:12888756 C>A), RS1003067446 (19:12889185 G>A), RS1004230112 (19:12885709 C>G,T), RS1004330846 (19:12886467 T>TGA), RS1004663054 (19:12884833 G>A,C), RS1004680080 (19:12886889 AC>A), RS1005324514 (19:12887405 T>C), RS1005706582 (19:12887174 C>T), RS1006300152 (19:12885791 C>A), RS1006688752 (19:12884368 C>A,G), RS1006742842 (19:12886004 C>A,T), RS1006969257 (19:12888693 A>T)

Disease associations

OMIM: gene MIM:600599 | disease phenotypes: MIM:620969, MIM:613673

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital dyserythropoietic anemia type 4	Definitive	Autosomal dominant
anemia, congenital dyserythropoietic, type IVb	Strong	Autosomal recessive
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome	Supportive	Autosomal recessive
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	Supportive	Autosomal dominant

Mondo (4): anemia, congenital dyserythropoietic, type IVb (MONDO:0975829), congenital dyserythropoietic anemia type 4 (MONDO:0013355), hereditary persistence of fetal hemoglobin-sickle cell disease syndrome (MONDO:0016672), hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome (MONDO:0018749)

Orphanet (2): Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome (Orphanet:251380), Congenital dyserythropoietic anemia type IV (Orphanet:293825)

HPO phenotypes

69 total (30 of 69 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000260	Wide anterior fontanel
HP:0000488	Retinopathy
HP:0000821	Hypothyroidism
HP:0000980	Pallor
HP:0001081	Cholelithiasis
HP:0001433	Hepatosplenomegaly
HP:0001639	Hypertrophic cardiomyopathy
HP:0001735	Acute pancreatitis
HP:0001744	Splenomegaly
HP:0001746	Asplenia
HP:0001789	Hydrops fetalis
HP:0001824	Weight loss
HP:0001878	Hemolytic anemia
HP:0001903	Anemia
HP:0001909	Leukemia
HP:0001923	Reticulocytosis
HP:0001971	Hypersplenism
HP:0001981	Schistocytosis
HP:0002007	Frontal bossing
HP:0002027	Abdominal pain
HP:0002113	Pulmonary infiltrates
HP:0002240	Hepatomegaly
HP:0002829	Arthralgia
HP:0002904	Hyperbilirubinemia
HP:0002908	Conjugated hyperbilirubinemia
HP:0003330	Abnormal bone structure

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002595_9	Clozapine-induced agranulocytosis	1.000000e-06
GCST004601_186	Red blood cell count	4.000000e-42
GCST004602_263	Mean corpuscular volume	3.000000e-79
GCST004605_77	Mean corpuscular hemoglobin concentration	1.000000e-16
GCST004619_109	Reticulocyte fraction of red cells	1.000000e-27
GCST004622_74	Reticulocyte count	2.000000e-19
GCST004630_58	Mean corpuscular hemoglobin	5.000000e-86
GCST006011_58	Mean corpuscular volume	4.000000e-32
GCST90002385_498	High light scatter reticulocyte count	1.000000e-47
GCST90002390_526	Mean corpuscular hemoglobin	4.000000e-121
GCST90002391_105	Mean corpuscular hemoglobin concentration	5.000000e-29
GCST90002392_65	Mean corpuscular volume	2.000000e-109
GCST90002396_20	Mean reticulocyte volume	3.000000e-34
GCST90002397_189	Mean spheric corpuscular volume	3.000000e-61
GCST90002403_278	Red blood cell count	6.000000e-68
GCST90002404_565	Red cell distribution width	3.000000e-31
GCST90002405_535	Reticulocyte count	6.000000e-49
GCST90002406_488	Reticulocyte fraction of red cells	6.000000e-40
GCST90002406_489	Reticulocyte fraction of red cells	3.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3407313 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
pomalidomide	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Hydrogen Peroxide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3411257	Binding	Inhibition of KLF1 (unknown origin) binding to DNA at 40 uM incubated for 4 hrs followed by biotin-labeled probes addition and incubated for another 1 hr by electromobility gel shift assay	Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory cell differentiation. — J Med Chem

Cellosaurus cell lines

11 cell lines: 6 induced pluripotent stem cell, 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_A3N1	SEES3-1V human KLF1, clone1	Embryonic stem cell	Male
CVCL_A3N2	SEES3-1V human KLF1, clone2	Embryonic stem cell	Male
CVCL_A3N3	SEES3-1V human KLF1, clone3	Embryonic stem cell	Male
CVCL_AW32	K562 eGFP-KLF1	Cancer cell line	Female
CVCL_B6RA	iKLF1.1	Induced pluripotent stem cell	Female
CVCL_B6RB	iKLF1.2	Induced pluripotent stem cell	Female
CVCL_B6RC	iKLF1.6	Induced pluripotent stem cell	Female
CVCL_B6RD	iKLF1.7	Induced pluripotent stem cell	Female
CVCL_B6RE	iKLF1.12	Induced pluripotent stem cell	Female
CVCL_HC79	HEK293 eGFP-KLF1	Transformed cell line	Female

Clinical trials (associated diseases)

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