Affinage

KLF1

Krueppel-like factor 1 · UniProt Q13351

Length
362 aa
Mass
38.2 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLF1 (EKLF) is the master transcriptional regulator of definitive erythropoiesis, coordinating nearly all aspects of terminal red cell maturation including globin production, heme biosynthesis, cell cycle exit, and membrane/cytoskeletal gene expression through genome-wide occupancy of CACCC/CACC elements (PMID:7753195, PMID:7753194, PMID:20508144, PMID:22835905). It binds the beta-globin CACCC element via its zinc fingers, where thalassemia point mutations that weaken binding abolish transactivation, and it directly activates the locus control region site 5'HS3 (PMID:8288615, PMID:9744863). KLF1 is embedded in the erythroid regulatory hierarchy downstream of GATA-1, which directly activates the EKLF promoter through a GATA-E box-GATA composite element, while KLF1 reciprocally interacts and synergizes with GATA-1 and stabilizes GATA-1/TAL1 occupancy, histone acetylation, and chromatin looping at target loci (PMID:7739528, PMID:8195185, PMID:9603943, PMID:10688820, PMID:18448565, PMID:25528728). Productive activation requires recruitment of a SWI/SNF-related chromatin remodeling complex (E-RC1/BRG1) to open chromatin at target promoters, and KLF1 functions as a pioneer factor controlling RNA polymerase II pause-release (PMID:9778250, PMID:36543143). KLF1 is a master switch for hemoglobin switching: it directly activates adult beta-globin while simultaneously activating the gamma-globin repressors BCL11A and ZBTB7A/LRF, and a British HPFH mutation creates a de novo KLF1 site that activates fetal globin (PMID:20676097, PMID:28659276, PMID:29296711). It drives terminal differentiation by directly activating cell-cycle regulators E2f2, p21, and the CDK inhibitors p18/p27, the latter being required for cell cycle exit and enucleation (PMID:18852285, PMID:19457859, PMID:20368355, PMID:27480112). KLF1 also enforces erythroid versus megakaryocyte lineage choice through mutual antagonism with FLI-1 and by repressing Fli-1, and it acts non-cell-autonomously in erythroblastic island macrophages by directly activating Dnase2a to enable degradation of extruded nuclei (PMID:12556498, PMID:17715392, PMID:21807894, PMID:33570494). Its activity is tuned by post-translational modifications: CBP/p300 acetylation at K288 toggles coactivator versus Sin3A/HDAC1 corepressor interactions and is required for chromatin opening, while PIAS1-mediated sumoylation enables NuRD/Mi-2beta-dependent repression (PMID:15542849, PMID:17938210, PMID:18710946).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Establishing how EKLF reaches its erythroid target and where it sits in the regulatory hierarchy was first addressed by defining its DNA element and its upstream activator.

    Evidence In vitro/in vivo binding and transactivation at the beta-globin CACCC element, and promoter dissection of the EKLF gene driven by GATA-1

    PMID:8195185 PMID:8288615

    Open questions at the time
    • Did not address chromatin context or cofactor requirements for transactivation
    • Genome-wide target spectrum unknown at this stage
  2. 1995 High

    Whether EKLF is functionally essential and how it cooperates with other erythroid factors was resolved by knockout and physical interaction studies.

    Evidence EKLF knockout mice (fatal anemia, beta-globin deficit) and Co-IP/synergy assays with GATA-1

    PMID:7739528 PMID:7753194 PMID:7753195

    Open questions at the time
    • Whether anemia stems from globin loss alone or other targets was unresolved
    • Mechanism of GATA-1/EKLF synergy on chromatin not defined
  3. 1996 Medium

    Dissection of the transactivation domain into stimulatory and inhibitory subdomains revealed that EKLF activity is conformationally gated and cofactor-dependent.

    Evidence Deletion/mutagenesis and DNA-binding competition assays of the proline-rich TAD

    PMID:8918466

    Open questions at the time
    • Identity of the positive-acting cellular factor not defined here
    • Single-lab functional mapping without structural data
  4. 1998 High

    How EKLF mechanically activates transcription on chromatin and how it is post-translationally controlled was established through chromatin remodeling, acetylation, and phosphorylation studies.

    Evidence In vitro chromatin-template reconstitution with purified E-RC1/SWI/SNF complex, CBP/p300/P-CAF acetylation assays, CKII phosphorylation and mutagenesis, and transgenic 5'HS3 specificity assays

    PMID:10688820 PMID:9603943 PMID:9707565 PMID:9722526 PMID:9744863 PMID:9778250

    Open questions at the time
    • Acetylated residue and its functional consequence not yet pinpointed
    • How PTMs integrate to switch activator/repressor states unresolved
  5. 2000 High

    Whether EKLF's essential role is reducible to globin regulation was tested by genetic complementation, establishing that non-globin targets are required for red cell function.

    Evidence Gamma-globin transgene complementation on EKLF-null background with hematological analysis

    PMID:10688844

    Open questions at the time
    • The specific essential non-globin targets were not identified here
  6. 2003 High

    The basis of erythroid versus megakaryocyte lineage decision was clarified by demonstrating mutual transcriptional antagonism between EKLF and FLI-1.

    Evidence Co-IP, Gal4-domain mapping, and reciprocal reporter repression assays

    PMID:12556498

    Open questions at the time
    • In vivo lineage consequences of the antagonism not measured in this study
  7. 2004 High

    How EKLF can both activate and repress was resolved by linking its acetylation status to a choice between coactivators and Sin3A/HDAC1 corepressors.

    Evidence Co-IP, point mutagenesis of a key lysine, and stage-specific repression assays

    PMID:15542849

    Open questions at the time
    • How stage-specific signals dictate acetylation state in vivo not defined
  8. 2006 Medium

    EKLF protein turnover was characterized, showing it is a short-lived, proteasome-degraded factor.

    Evidence Proteasome inhibition, in vivo ubiquitination, pulse-chase stability, and PEST mutagenesis

    PMID:16579989

    Open questions at the time
    • The responsible E3 ligase was not identified
    • Physiological signals controlling turnover unknown
  9. 2008 High

    EKLF's roles in cell cycle progression, in transcriptional networks with other KLFs, in repression via sumoylation, and in upstream induction were defined through ChIP, genetic, and PTM studies.

    Evidence ChIP at E2f2 promoter with cell-cycle phenotyping, KLF3 promoter competition with Klf3-KO analysis, PIAS1-mediated sumoylation/NuRD co-IP, K288 acetylation ChIP rescue, Gata2/Smad5-driven Eklf induction, and demonstration of a cytoplasmic EKLF pool

    PMID:17938210 PMID:18329016 PMID:18448565 PMID:18687676 PMID:18710946 PMID:18852285

    Open questions at the time
    • Functional role of the cytoplasmic EKLF pool not established
    • How acetylation/sumoylation are coordinated in vivo unresolved
  10. 2009 High

    Direct genetic linkage between EKLF, E2f2, and cell cycle entry was established, and EKLF was shown to act as a gamma-globin co-activator under SCFA induction.

    Evidence ChIP at E2f2 intronic enhancers with Rb-knockout epistasis rescue, and EKLF/BRG1 recruitment at the gamma-globin promoter

    PMID:19220418 PMID:19457859

    Open questions at the time
    • Context-dependence of EKLF acting at gamma-globin versus repressing it via BCL11A not reconciled here
  11. 2010 High

    Genome-wide occupancy and the globin-switching mechanism were defined, establishing KLF1 as a global activator and a dual controller of hemoglobin switching.

    Evidence KLF1 ChIP-seq in primary fetal liver erythroid cells, BCL11A knockdown studies, p21 ChIP/reporter assays, dematin/cytoskeletal target profiling, and c-Myb-driven KLF1 activation

    PMID:16380451 PMID:20368355 PMID:20508144 PMID:20676097 PMID:20686118

    Open questions at the time
    • Direct functional dissection of most of the >945 binding sites not performed
    • Hierarchy among the many activated programs not ranked
  12. 2011 High

    The structural basis of TAD-cofactor contacts, KLF1's role in macrophage Dnase2a regulation, and synergy with KLF2 at Myc were defined.

    Evidence NMR structure of EKLFTAD2/Tfb1PH with CBP/p300 binding, ChIP at the macrophage Dnase2a promoter with KO analysis, and KLF1/KLF2 ChIP/Myc epistasis

    PMID:21670263 PMID:21807894 PMID:22566683

    Open questions at the time
    • Structural model limited to TAD2/Tfb1PH; full coactivator complex geometry unknown
    • Non-cell-autonomous macrophage contribution not quantitatively separated from intrinsic role
  13. 2012 High

    Integrated transcriptomic and genetic studies extended KLF1's regulatory reach to a cis-regulatory module shared with GATA1/TAL1/EP300, to feedback repressor KLF3, and to PIT1.

    Evidence mRNA-seq of Klf1+/+ vs Klf1-/- integrated with ChIP-seq, Klf3-KO profiling, and PIT1 ChIP/shRNA/rescue

    PMID:22711990 PMID:22835905 PMID:23190530

    Open questions at the time
    • Functional roles of KLF1-dependent lncRNAs not characterized
    • How activating and repressive KLF subnetworks balance quantitatively unresolved
  14. 2014 Medium

    KLF1's mechanism of stabilizing partner-factor occupancy, its assembly into an HDAC (NuRSERY) complex, and its macrophage-extrinsic role were further detailed.

    Evidence ChIP after KLF1 knockdown showing reduced GATA-1/TAL1 binding, NuRSERY complex Co-IP with ERK-dependence, and embryoid-body island formation with EKLF macrophage marking

    PMID:24594363 PMID:24866116 PMID:25528728

    Open questions at the time
    • NuRSERY complex functional output partially inferred from pharmacology
    • Mechanism by which KLF1 stabilizes partner occupancy not structurally defined
  15. 2016 High

    The causal link between KLF1-controlled cell cycle exit and enucleation was established by epistatic rescue.

    Evidence Imaging flow cytometry of terminal differentiation with p18/p27 reintroduction rescue in EKLF-deficient cells

    PMID:27480112

    Open questions at the time
    • Direct ChIP occupancy at p18/p27 loci not the focus of this study
    • Mechanical link between cell cycle exit and nuclear extrusion machinery not defined
  16. 2017 Medium

    Direct activation of the gamma-globin repressor ZBTB7A and the gain-of-binding HPFH mechanism cemented KLF1's central role in fetal-to-adult globin switching.

    Evidence ZBTB7A promoter ChIP/reporter assays and CRISPR introduction of the -198 T>C gamma-globin promoter variant in HUDEP-2 cells

    PMID:28659276 PMID:29296711

    Open questions at the time
    • Quantitative contribution of ZBTB7A vs BCL11A to switching not resolved here
  17. 2021 High

    Single-cell profiling defined KLF1-expressing erythroblastic island macrophages as a discrete transient population with KLF1-dependent gene clusters.

    Evidence Single-cell RNA-seq with genetic EKLF marking and KO analysis in fetal liver

    PMID:33570494

    Open questions at the time
    • Functional necessity of individual KLF1-dependent macrophage genes for island integrity not dissected
  18. 2022 High

    KLF1 was defined as a pioneer factor acting through Pol II pause-release, and the Nan/+ variant was shown to drive neomorphic binding and target activation.

    Evidence ChIP-seq and GRO-seq/Pol II occupancy in wild-type and Nan/+ (E339D) erythroid cells

    PMID:36543143

    Open questions at the time
    • Generalizability of pioneering across all KLF1 sites not established
    • Molecular basis of Nan-EKLF enhancer redirection not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many KLF1 post-translational modifications, partner-stabilizing functions, and pioneering activity are integrated in real time to switch between activator and repressor states across erythroid maturation stages remains unresolved.
  • No unified model linking acetylation, sumoylation, phosphorylation, and turnover to stage-specific output
  • Quantitative hierarchy among hundreds of direct targets undefined
  • E3 ligase and signaling control of KLF1 abundance unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3
Partners
BRG1CBPEP300FLI1GATA1PIAS1SIN3ATAL1
Complex memberships
E-RC1 (SWI/SNF/BRG1)NuRD (Mi-2beta)NuRSERY (HDAC5/GATA1/EKLF/pERK)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 EKLF/KLF1 knockout mice die of anemia during fetal liver erythropoiesis with specific deficit in beta-globin gene expression, establishing that EKLF is required for definitive erythropoiesis and beta-globin activation but is dispensable for yolk sac erythropoiesis and erythroid commitment. Gene targeting (knockout mouse), hematological and molecular phenotyping Nature High 7753194 7753195
1994 EKLF binds the CACCC element in the beta-globin promoter via its zinc finger domain; beta-thalassemia point mutations in the CAC site reduce EKLF binding affinity 40–100-fold and abolish EKLF-dependent transactivation, demonstrating that EKLF binding to CACCC is essential for beta-globin transcription. In vivo reporter transactivation assays, in vitro DNA binding affinity measurements, molecular modeling based on Zif268/DNA co-crystal structure The Journal of biological chemistry High 8288615
1995 EKLF physically interacts with the erythroid transcription factor GATA-1 through their respective DNA-binding domains; GATA-1 and EKLF synergize to activate transcription, providing a mechanism for erythroid-specific gene regulation. Co-immunoprecipitation, in vitro binding assays, co-transfection transcriptional synergy assays Molecular and cellular biology High 7739528
1994 GATA-1 directly activates the EKLF gene promoter through a GATA motif at position -60; GATA-1 binding sites and CP1 sites are both required for full EKLF promoter activity, placing EKLF downstream of GATA-1 in the erythroid regulatory hierarchy. Promoter deletion/mutation analysis, co-transfection assays, DNA binding assays The Journal of biological chemistry High 8195185
1998 EKLF is acetylated in vivo and interacts with histone acetyltransferases CBP, p300, and P/CAF; CBP and p300 (but not P/CAF) acetylate EKLF within its transactivation domain and enhance EKLF-dependent beta-globin transcription in erythroid cells. In vivo co-immunoprecipitation, in vitro acetylation assay, co-transfection transcriptional activation assays Proceedings of the National Academy of Sciences of the United States of America High 9707565
1998 EKLF requires a SWI/SNF-related chromatin remodeling complex (E-RC1, containing BRG1, BAF170, BAF155, INI1, and BAF57) to remodel chromatin at the beta-globin promoter and activate transcription in vitro; this interaction is transcription-factor selective. In vitro chromatin-assembled transcription assay, biochemical purification of E-RC1 complex, functional reconstitution Cell High 9778250
1998 EKLF is phosphorylated at serine and threonine residues within its transactivation region; casein kinase II (CKIIα) interacts with EKLF and phosphorylates Thr-41 within the EKLF interaction domain, and mutation of this CKII site abolishes EKLF transactivation activity. In vivo phosphorylation analysis, in vitro kinase assay, site-directed mutagenesis, co-transfection transcriptional assays The Journal of biological chemistry High 9722526
1996 EKLF's proline-rich transactivation domain contains discrete stimulatory and inhibitory subdomains; the inhibitory domain suppresses DNA binding in cis, while a 40 amino acid minimal transactivation domain mediates trans-interaction with a positive-acting cellular factor, and phosphorylation/conformation of this core is critical for these interactions. Deletion/mutagenesis co-transfection assays, in vitro DNA binding competition assays, in vivo competition assays The EMBO journal Medium 8918466
1998 The mouse EKLF promoter contains a GATA-E box-GATA composite element in which GATA-1 binds both GATA sites and another erythroid factor binds the central E box; all three sites act as a unit (not additively) to drive erythroid-specific EKLF expression in transgenic mice. Transgenic mouse reporter assays, in vitro DNA binding/gel-shift assays, promoter mutagenesis The Journal of biological chemistry High 10688820 9603943
1998 EKLF activates the beta-globin locus control region hypersensitive site 5'HS3 in vivo, as demonstrated by matching point mutations in 5'HS3 CACCC motifs with amino acid substitutions in EKLF zinc fingers that alter DNA-binding specificity. Altered DNA-binding specificity approach (matched mutations in DNA site and zinc finger), transgenic mouse assay Genes & development High 9744863
2004 EKLF functions as a stage-specific transcriptional repressor in addition to an activator; it interacts with Sin3A and HDAC1 corepressors via its zinc finger domain, and a key lysine residue serves as both a CBP acetylation substrate and a Sin3A interaction site, linking acetylation status to coactivator vs. corepressor choice. Co-immunoprecipitation, point mutagenesis, in vivo transcriptional repression assays, stage-specific erythroid cell assays Molecular and cellular biology High 15542849
2007 EKLF is post-translationally modified by sumoylation at a single site near its amino terminus; PIAS1 is the SUMO E3 ligase for this modification. Sumoylation is required for EKLF's repressive (not activating) function through a SUMO-dependent interaction with the Mi-2β component of the NuRD repression complex, and is important for inhibiting megakaryocyte differentiation. In vivo sumoylation assay, site-directed mutagenesis, co-immunoprecipitation, gain/loss-of-function transcriptional and lineage differentiation assays Molecular and cellular biology High 17938210
2003 FLI-1 represses EKLF-dependent transcription by interacting with EKLF (via FLI-1 N- and C-terminal domains) and recruiting the repressive FLI-1 ETS domain to erythroid promoters; reciprocally, EKLF represses the FLI-1-dependent megakaryocytic GPIX promoter, establishing functional cross-antagonism that controls erythroid vs. megakaryocytic lineage choice. Co-immunoprecipitation, reporter gene transcription assays, Gal4-fusion domain analysis Molecular and cellular biology High 12556498
2007 EKLF plays a directive role in megakaryocyte-erythroid progenitor lineage commitment: EKLF inhibits megakaryocyte formation while stimulating erythroid differentiation, at least partly by repressing Fli-1 mRNA levels, and is uniquely down-regulated in megakaryocytes after MEP formation. Gain- and loss-of-function studies in hematopoietic progenitors, expression profiling, molecular analyses of Fli-1 expression Blood High 17715392
2008 EKLF is required for cell cycle progression in erythroid progenitors; loss of EKLF leads to reduced E2f2 (and E2f4) expression, G1-to-S phase delay, and failure of terminal differentiation. EKLF directly occupies the E2f2 proximal promoter in vivo and its binding correlates with DNase I sensitivity. ChIP assay, transcriptional profiling, cell cycle analysis, EKLF-null mouse analysis Molecular and cellular biology High 18852285
2009 EKLF directly regulates E2f2 via novel intronic enhancers containing conserved CACC/GATA/E-box elements that are occupied by EKLF in vivo; genetic depletion of Rb in EKLF(-/-) fetal liver partially rescues the cell cycle defect, establishing epistatic linkage between EKLF, E2f2, and cell cycle entry. ChIP assay, reporter gene assays, genetic epistasis (Rb knockout rescue), cell cycle analysis The Journal of biological chemistry High 19457859
2010 KLF1 directly activates BCL11A expression in erythroid cells; KLF1 knockdown reduces BCL11A levels and increases gamma-globin/beta-globin expression ratios, establishing that KLF1 controls globin switching by directly activating beta-globin AND indirectly repressing gamma-globin via BCL11A. shRNA knockdown in human and mouse adult erythroid progenitors, gene expression analysis Nature genetics High 20676097
2008 KLF1 activates Klf8 gene expression through CACCC sites in both Klf8 promoters; KLF3 competes with KLF1 at these sites to repress Klf8; in Klf3 knockout tissue, KLF1 gains access and activates Klf8 promoters, revealing a direct competitive network between activating (KLF1) and repressing (KLF3) Krüppel-like factors. Chromatin immunoprecipitation (ChIP), reporter gene assays, Klf3 knockout mouse analysis, promoter competition analysis The Journal of biological chemistry High 18687676
2008 EKLF acetylation at lysine 288 is essential for recruitment of CBP to the beta-globin locus, histone H3 modification, chromatin opening (DNase I sensitivity), and beta-globin transcription. EKLF's zinc finger domain associates specifically with the histone H3 amino terminus, and H3.3 (not H3.1) is enriched at the beta-globin promoter in an EKLF-dependent manner. Retroviral EKLF rescue of EKLF-null erythroid line, ChIP, DNase I sensitivity assay, site-directed mutagenesis of K288 Molecular and cellular biology High 18710946
2002 BMP4 signaling through the BMP/Smad pathway is necessary and sufficient to induce EKLF (and GATA1) expression during embryoid body differentiation; dominant-negative BMP receptor or inhibitory Smad6 prevents EKLF induction even in serum, establishing the BMP/Smad pathway as upstream of EKLF expression onset. Serum-free embryoid body differentiation, BMP4 treatment, dominant-negative receptor/Smad6 expression in ES cells Development (Cambridge, England) High 11807044
2008 Gata2 and Smad5 cooperate to induce Eklf expression in hematopoietic progenitors prior to erythroid commitment; upon erythroid commitment, regulation switches to Gata1-controlled Eklf transcription. Transgenic reporter assays in differentiating ES cells and fetal liver, phylogenetic footprinting, in vivo ChIP-like binding studies, loss-of-function in embryoid bodies Development (Cambridge, England) High 18448565
2010 KLF1 has at least 945 genomic binding sites in E14.5 fetal liver erythroid cells; it occupies promoters of erythroid genes including Hbb-b1 and acts primarily as a transcriptional activator coordinating nearly all aspects of terminal erythroid differentiation including globin production, heme biosynthesis, cell cycle, and red cell membrane/cytoskeleton genes. KLF1 ChIP-seq in primary mouse erythroid cells Genome research High 20508144
2010 EKLF directly activates p21(WAF1/CIP1) expression independently of p53 through binding to CACCC motifs in the proximal p21 promoter and a novel conserved intronic region downstream of the TATA box, linking EKLF to cell cycle exit during erythroid maturation. ChIP assay, promoter-reporter assays with mutational analysis Molecular and cellular biology High 20368355
2011 EKLF's minimal transactivation domain (TAD) contains two functional subdomains (TAD1 and TAD2); TAD2 binds the PH domain of the Tfb1/p62 subunit of TFIIH and four domains of CBP/p300. NMR structure of EKLFTAD2/Tfb1PH complex shows TAD2 binds in an extended conformation (distinct from p53TAD2 alpha-helical binding). NMR structure determination, in vitro binding assays, sequence/functional domain analysis Proceedings of the National Academy of Sciences of the United States of America High 21670263
2006 EKLF/KLF1 protein is ubiquitinated in vivo and degraded by the 26S proteasome; EKLF half-life is less than 3 hours in MEL cells and 6–9 hours in fetal liver cells; ubiquitination does not require a specific internal lysine, and PEST sequences within the N-terminus contribute to protein destabilization. Proteasome inhibitor treatment, in vivo ubiquitination assay, pulse-chase protein stability assay, PEST sequence mutagenesis FEBS letters Medium 16579989
2008 A substantial proportion of endogenous EKLF resides in the cytoplasm at steady state in erythroid cells, not solely in the nucleus; EKLF can shuttle out of the nucleus (demonstrated by heterokaryon assay) with rapid nuclear re-entry; nuclear vs. cytoplasmic EKLF shows subtle biochemical and functional differences. Subcellular fractionation, heterokaryon shuttle assay, CRM1 inhibition assay Experimental cell research Medium 18329016
2016 EKLF/KLF1 directly regulates p18 and p27 CDK inhibitor expression to control cell cycle exit; loss of EKLF leads to a block at the orthochromatic erythroblast stage with failure of enucleation; reintroduction of either p18 or p27 rescues both cell cycle and enucleation deficits, establishing that EKLF-controlled cell cycle exit is required for enucleation. Imaging flow cytometry, ex vivo terminal erythroid differentiation culture, epistatic rescue experiments with p18/p27 reintroduction Blood High 27480112
2010 EKLF is required for proper expression of erythrocyte cytoskeletal protein dematin (band 4.9); EKLF occupies conserved CACC motifs in the dematin gene in vivo and activates transcription through these elements; EKLF also regulates alpha-hemoglobin stabilizing protein (AHSP), cytoskeletal proteins, heme synthesis enzymes, and blood group antigens. ChIP assay, promoter reporter assay, expression profiling of EKLF-null fetal liver and EKLF-ER inducible cell lines Blood High 16380451
2011 KLF1 directly binds and activates the Dnase2a promoter in the central macrophage of erythroblastic islands; Dnase2a is severely downregulated in Klf1 KO fetal liver; KLF1 is expressed in erythroblastic island macrophages and exerts a non-cell-autonomous role in erythropoiesis by enabling degradation of extruded erythroid nuclei. ChIP assay (KLF1 occupancy at Dnase2a promoter), KO mouse analysis, expression analysis Molecular and cellular biology High 21807894
2014 EKLF/KLF1 is expressed in erythroblastic island macrophages (derived from erythro-myeloid progenitors) and plays an extrinsic role in erythroid maturation by regulating genes important for island integrity within macrophage cells, in addition to its intrinsic role in erythroid progenitors. Embryoid body single-progenitor island formation assay, genetic lineage marking, expression analysis in EKLF-expressing macrophages vs. EKLF-null cells Development (Cambridge, England) Medium 24866116
2009 EKLF is recruited to the gamma-globin promoter in primary human erythroid progenitors upon SCFA derivative treatment, functioning as a co-activator for gamma-globin induction; EKLF knockdown prevents SCFA-induced gamma-globin expression; BRG1 is co-recruited to the gamma-globin promoter in an EKLF-dependent manner. ChIP assay (endogenous promoter), siRNA knockdown, gamma-globin reporter assay European journal of haematology Medium 19220418
2012 KLF1 directly drives dematin and a broad transcriptome of erythroid genes through a cis-regulatory module co-occupied by KLF1, GATA1, TAL1, and EP300; KLF1 is required for expression of novel lncRNAs and directs apoptotic gene expression during terminal erythroid maturation; KLF1 also drives erythroid-specific promoters of ubiquitous genes. mRNA-seq comparison of Klf1(+/+) vs. Klf1(-/-) erythroid tissue, integration with prior KLF1 ChIP-seq data Genome research High 22835905
2012 c-Myb directly binds the KLF1 promoter and transactivates KLF1 expression; ChIP and luciferase reporter assays demonstrate this direct regulation; KLF1 overexpression can partially rescue the erythroid defect and megakaryocyte bias caused by c-Myb silencing. ChIP assay, luciferase reporter assay, retroviral overexpression rescue experiments Blood High 20686118
2014 KLF1 stabilizes GATA-1 and TAL1 occupancy at the beta-globin locus and other erythroid genes; KLF1 knockdown reduces GATA-1 and TAL1 chromatin binding without affecting their protein levels, and abolishes histone acetylation and chromatin looping at target loci. KLF1 stable knockdown in K562 cells, ChIP assay for multiple factors and histone marks Biochimica et biophysica acta Medium 25528728
2014 In erythroid cells, EKLF forms a novel HDAC complex (NuRSERY) containing HDAC5, GATA1, EKLF, and phospho-ERK (pERK); this complex is absent in megakaryocytic cells; ERK phosphorylation is required for complex formation and nuclear localization of HDAC5, GATA1, and EKLF. Pulldown/co-immunoprecipitation, ERK inhibitor treatment, Western blot analysis The international journal of biochemistry & cell biology Medium 24594363
2017 The British HPFH mutation (-198 T>C in the gamma-globin promoter) creates a de novo KLF1 binding site, and KLF1 directly binds this site to activate fetal globin expression; CRISPR introduction of -198 C into HUDEP-2 cells substantially elevates HbF. CRISPR/Cas9 genome editing, in vitro and in vivo binding assays, reporter assays Blood High 28659276
2017 KLF1 directly activates ZBTB7A/LRF expression in erythroid cells by binding to the ZBTB7A proximal promoter; KLF1 also drives expression of a novel erythroid-specific ZBTB7A transcript, establishing ZBTB7A as a KLF1 target gene involved in gamma-globin repression. ChIP assay, promoter reporter assay, expression analysis Blood advances Medium 29296711
2022 EKLF/KLF1 acts as a pioneer transcription factor and regulates transcription through selective RNA polymerase II pause-release; in the Nan/+ mouse (EKLF-E339D variant), Nan-EKLF limits normal EKLF binding at a subset of sites and ectopically binds largely at enhancers, activating neomorphic target genes through pioneering and Pol II pause-release mechanisms. ChIP-seq in wild-type and Nan/+ mouse embryonic erythroid cells, GRO-seq/RNA Pol II occupancy analysis Cell reports High 36543143
2000 Correction of globin chain imbalance in EKLF-null embryos by gamma-globin transgene does not correct hemolysis or extend survival, establishing that nonglobin EKLF target genes are essential for definitive red blood cell function. Genetic complementation (gamma-globin transgene on EKLF-null background), hematological analysis Blood High 10688844
2012 EKLF directly activates the Klf3 gene, which then represses a subset of KLF1 target genes; KLF3 knockout mice exhibit impaired erythroid maturation, and KLF3 acts primarily as a feedback repressor countering EKLF activity at selected erythroid target genes. Klf3 knockout mouse analysis, microarray expression profiling, promoter analysis Molecular and cellular biology Medium 22711990
2012 EKLF directly activates PIT1/SLC20A1 expression during RBC maturation by binding to the PIT1 promoter in vivo; shRNA depletion of either PIT1 or EKLF impairs erythroid maturation, and re-expression of PIT1 in EKLF-depleted cells partially restores maturation. ChIP assay (EKLF at PIT1 promoter), shRNA knockdown, epistatic rescue by PIT1 re-expression Blood High 23190530
2011 KLF1 directly activates KLF2 expression and binds Myc promoters; KLF1 and KLF2 synergistically regulate Myc expression in embryonic erythroid cells; Myc ablation in embryonic proerythroblasts recapitulates KLF1/KLF2 double-KO anemia phenotype. Expression profiling, ChIP assay, genetic epistasis (Myc conditional KO in erythroid cells) Molecular and cellular biology Medium 22566683
2021 EKLF/KLF1 expression defines a unique macrophage subset (erythroblastic island macrophages) during fetal liver erythropoiesis; single-cell sequencing identifies EKLF-dependent gene clusters and novel cell surface biomarkers specific to this macrophage population, which appears transiently during embryogenesis. Single-cell RNA-seq, global sequencing, genetic EKLF marking and KO analysis eLife High 33570494

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature 536 7753195
1995 Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature 496 7753194
1995 Functional synergy and physical interactions of the erythroid transcription factor GATA-1 with the Krüppel family proteins Sp1 and EKLF. Molecular and cellular biology 430 7739528
2010 KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nature genetics 320 20676097
1998 Acetylation and modulation of erythroid Krüppel-like factor (EKLF) activity by interaction with histone acetyltransferases. Proceedings of the National Academy of Sciences of the United States of America 320 9707565
1998 A SWI/SNF-related chromatin remodeling complex, E-RC1, is required for tissue-specific transcriptional regulation by EKLF in vitro. Cell 265 9778250
2011 The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood 260 21613252
2010 A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells. Genome research 191 20508144
1996 The role of EKLF in human beta-globin gene competition. Genes & development 180 8918890
2005 A global role for EKLF in definitive and primitive erythropoiesis. Blood 176 16380451
1994 Analyses of beta-thalassemia mutant DNA interactions with erythroid Krüppel-like factor (EKLF), an erythroid cell-specific transcription factor. The Journal of biological chemistry 167 8288615
2010 A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. American journal of human genetics 159 21055716
2014 KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of β-thalassemia. Blood 138 24829204
2005 The erythroid phenotype of EKLF-null mice: defects in hemoglobin metabolism and membrane stability. Molecular and cellular biology 135 15923635
2016 Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants. Blood 134 26903544
1996 Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF. Proceedings of the National Academy of Sciences of the United States of America 129 8901569
2008 Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype. Blood 123 18487511
2003 Functional cross-antagonism between transcription factors FLI-1 and EKLF. Molecular and cellular biology 114 12556498
2007 Novel role for EKLF in megakaryocyte lineage commitment. Blood 110 17715392
1994 Regulation of the erythroid Kruppel-like factor (EKLF) gene promoter by the erythroid transcription factor GATA-1. The Journal of biological chemistry 103 8195185
2012 Prediction of novel long non-coding RNAs based on RNA-Seq data of mouse Klf1 knockout study. BMC bioinformatics 96 23237380
2010 c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression. Blood 93 20686118
2012 Novel roles for KLF1 in erythropoiesis revealed by mRNA-seq. Genome research 92 22835905
2011 KLF1 gene mutations cause borderline HbA(2). Blood 91 21821711
2008 A network of Krüppel-like Factors (Klfs). Klf8 is repressed by Klf3 and activated by Klf1 in vivo. The Journal of biological chemistry 91 18687676
2008 Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2. Molecular and cellular biology 87 18852285
2017 KLF1 drives the expression of fetal hemoglobin in British HPFH. Blood 79 28659276
2002 The BMP/BMPR/Smad pathway directs expression of the erythroid-specific EKLF and GATA1 transcription factors during embryoid body differentiation in serum-free media. Development (Cambridge, England) 78 11807044
2015 KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome. Blood 77 25724378
1996 Isolation, genomic structure, and expression of human erythroid Krüppel-like factor (EKLF). DNA and cell biology 77 8924208
2016 EKLF/KLF1-regulated cell cycle exit is essential for erythroblast enucleation. Blood 75 27480112
2008 EKLF restricts megakaryocytic differentiation at the benefit of erythrocytic differentiation. Blood 75 18523154
2001 Erythroid Kruppel-like factor (EKLF) coordinates erythroid cell proliferation and hemoglobinization in cell lines derived from EKLF null mice. Blood 73 11238130
2012 EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Molecular and cellular biology 70 23090966
2010 KLF1 directly coordinates almost all aspects of terminal erythroid differentiation. IUBMB life 69 21190291
1998 Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5'HS3 of the beta-globin locus control region. The EMBO journal 67 9545245
2009 EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2. The Journal of biological chemistry 66 19457859
2000 Context-dependent EKLF responsiveness defines the developmental specificity of the human epsilon-globin gene in erythroid cells of YAC transgenic mice. Genes & development 65 11069894
2011 Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin. Haematologica 64 21273267
2011 Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults. Haematologica 64 22102705
2007 Sumoylation of EKLF promotes transcriptional repression and is involved in inhibition of megakaryopoiesis. Molecular and cellular biology 63 17938210
2004 Stage-specific repression by the EKLF transcriptional activator. Molecular and cellular biology 63 15542849
2013 Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. Blood cells, molecules & diseases 61 23522491
1998 Multiple proteins binding to a GATA-E box-GATA motif regulate the erythroid Krüppel-like factor (EKLF) gene. The Journal of biological chemistry 60 9603943
1996 Erythroid Krüppel-like factor (EKLF) contains a multifunctional transcriptional activation domain important for inter- and intramolecular interactions. The EMBO journal 58 8918466
1998 Altered DNA-binding specificity mutants of EKLF and Sp1 show that EKLF is an activator of the beta-globin locus control region in vivo. Genes & development 55 9744863
2008 Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment. Development (Cambridge, England) 51 18448565
1998 Regulation of erythroid Krüppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. The Journal of biological chemistry 51 9722526
2011 Structural and functional characterization of an atypical activation domain in erythroid Kruppel-like factor (EKLF). Proceedings of the National Academy of Sciences of the United States of America 50 21670263
2020 Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin. Scientific reports 49 32576837
2016 Hydroxyurea down-regulates BCL11A, KLF-1 and MYB through miRNA-mediated actions to induce γ-globin expression: implications for new therapeutic approaches of sickle cell disease. Clinical and translational medicine 49 27056246
2017 KLF1 directly activates expression of the novel fetal globin repressor ZBTB7A/LRF in erythroid cells. Blood advances 48 29296711
2014 Induction of adult levels of β-globin in human erythroid cells that intrinsically express embryonic or fetal globin by transduction with KLF1 and BCL11A-XL. Haematologica 47 25107887
2000 Fetal expression of a human Agamma globin transgene rescues globin chain imbalance but not hemolysis in EKLF null mouse embryos. Blood 46 10688844
2013 Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice. Blood 45 23361909
2017 Activation of KLF1 Enhances the Differentiation and Maturation of Red Blood Cells from Human Pluripotent Stem Cells. Stem cells (Dayton, Ohio) 43 28026072
2017 Orchestration of late events in erythropoiesis by KLF1/EKLF. Current opinion in hematology 43 28157724
2016 Genetic disruption of the KLF1 gene to overexpress the γ-globin gene using the CRISPR/Cas9 system. The journal of gene medicine 42 27668420
2015 Krüppel-like factor 1: hematologic phenotypes associated with KLF1 gene mutations. International journal of laboratory hematology 42 25976964
2011 Mutations in the second zinc finger of human EKLF reduce promoter affinity but give rise to benign and disease phenotypes. Blood 42 21778342
2000 The GATA-E box-GATA motif in the EKLF promoter is required for in vivo expression. Blood 42 10688820
2011 Klf1 affects DNase II-alpha expression in the central macrophage of a fetal liver erythroblastic island: a non-cell-autonomous role in definitive erythropoiesis. Molecular and cellular biology 41 21807894
2006 Major erythrocyte membrane protein genes in EKLF-deficient mice. Experimental hematology 41 16728274
2022 Knockdown of lncRNA PCAT6 suppresses the growth of non-small cell lung cancer cells by inhibiting macrophages M2 polarization via miR-326/KLF1 axis. Bioengineered 40 35609331
2012 The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo. Molecular and cellular biology 39 22711990
2011 Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta-globin genes through direct promoter binding. The Journal of biological chemistry 39 21610079
2010 Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model. Genomics 38 20691777
1997 A shortened life span of EKLF-/- adult erythrocytes, due to a deficiency of beta-globin chains, is ameliorated by human gamma-globin chains. Blood 37 9242564
2012 Kruppel-like factor 1 (KLF1), KLF2, and Myc control a regulatory network essential for embryonic erythropoiesis. Molecular and cellular biology 36 22566683
2010 Dose-dependent regulation of primitive erythroid maturation and identity by the transcription factor Eklf. Blood 36 20720183
2009 Megakaryocyte-erythroid lineage promiscuity in EKLF null mouse blood. Haematologica 36 19850899
2005 Lyn deficiency reduces GATA-1, EKLF and STAT5, and induces extramedullary stress erythropoiesis. Oncogene 34 15516974
2010 EKLF directly activates the p21WAF1/CIP1 gene by proximal promoter and novel intronic regulatory regions during erythroid differentiation. Molecular and cellular biology 33 20368355
2014 Extrinsic and intrinsic control by EKLF (KLF1) within a specialized erythroid niche. Development (Cambridge, England) 32 24866116
2004 A novel silent beta-thalassemia mutation in the distal CACCC box affects the binding and responsiveness to EKLF. British journal of haematology 31 15352994
2008 Acetylation of EKLF is essential for epigenetic modification and transcriptional activation of the beta-globin locus. Molecular and cellular biology 30 18710946
2019 KLF-1 orchestrates a xenobiotic detoxification program essential for longevity of mitochondrial mutants. Nature communications 29 31346165
2015 Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin. European journal of human genetics : EJHG 29 25585695
2009 Clinical significance of Gata-1, Gata-2, EKLF, and c-MPL expression in acute myeloid leukemia. American journal of hematology 29 19097174
1998 Chromatin structure and transcriptional control elements of the erythroid Krüppel-like factor (EKLF) gene. The Journal of biological chemistry 29 9737959
2014 Identification of NuRSERY, a new functional HDAC complex composed by HDAC5, GATA1, EKLF and pERK present in human erythroid cells. The international journal of biochemistry & cell biology 27 24594363
2014 KLF1 stabilizes GATA-1 and TAL1 occupancy in the human β-globin locus. Biochimica et biophysica acta 27 25528728
2021 EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis. eLife 26 33570494
2009 Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. European journal of haematology 26 19220418
2004 Regulatory elements of the EKLF gene that direct erythroid cell-specific expression during mammalian development. Blood 26 14764531
2018 miR-326 regulates HbF synthesis by targeting EKLF in human erythroid cells. Experimental hematology 25 29601850
2012 EKLF-driven PIT1 expression is critical for mouse erythroid maturation in vivo and in vitro. Blood 25 23190530
1998 Transcription factor erythroid Krüppel-like factor (EKLF) is essential for the erythropoietin-induced hemoglobin production but not for proliferation, viability, or morphological maturation. The Journal of biological chemistry 25 9726989
2011 Delayed fetal hemoglobin switching in subjects with KLF1 gene mutation. Blood cells, molecules & diseases 23 22093801
2006 EKLF/KLF1 is ubiquitinated in vivo and its stability is regulated by activation domain sequences through the 26S proteasome. FEBS letters 23 16579989
1972 Genetic and physicochemical characterization of Escherichia coli strains carrying fused F' elements derived from KLF1 and F57. Proceedings of the National Academy of Sciences of the United States of America 22 4556462
2022 EKLF/Klf1 regulates erythroid transcription by its pioneering activity and selective control of RNA Pol II pause-release. Cell reports 21 36543143
2017 Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development. Development (Cambridge, England) 21 28143845
2014 Krüppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation. Haematologica 21 25150253
2013 Klf1, a C2H2 zinc finger-transcription factor, is required for cell wall maintenance during long-term quiescence in differentiated G0 phase. PloS one 21 24167631
2019 Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient. Haematologica 20 30872368
2019 KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells. Experimental hematology 20 30876823
2012 Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin. Annals of hematology 20 23161389
2008 Non-random subcellular distribution of variant EKLF in erythroid cells. Experimental cell research 20 18329016
2018 Differential role of Kruppel like factor 1 (KLF1) gene in red blood cell disorders. Genomics 19 30529538

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