Affinage

CEBPA

CCAAT/enhancer-binding protein alpha · UniProt P49715

Length
358 aa
Mass
37.6 kDa
Annotated
2026-06-09
100 papers in source corpus 25 papers cited in narrative 25 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

CEBPA encodes a basic-region leucine-zipper (bZIP) transcription factor that binds CCAAT/enhancer DNA elements and orchestrates lineage-specific gene programs across metabolism, hematopoiesis, and epithelial differentiation (PMID:2850264, PMID:1892816). Its DNA-binding domain adopts an 'induced helical fork' conformation, becoming fully alpha-helical only upon engaging a specific recognition sequence (PMID:1892816). C/EBPalpha functions combinatorially: it homo- and heterodimerizes with other C/EBP family members (PMID:1840554), cooperates with c-Myb and PU.1 to build myeloid enhancers and with PU.1 to specify cell-type-restricted NF-kappaB targeting (PMID:8756629, PMID:21402921), partners with PPARgamma at thousands of shared sites to drive adipogenesis (PMID:18981473), and recruits lineage factors such as NKX2-1 to enforce alveolar type 2 identity (PMID:38755149). In liver it is essential for energy homeostasis, controlling glycogen storage, gluconeogenic enzymes, and bilirubin conjugation (PMID:7652557, PMID:9315660). In hematopoiesis it maintains adult HSC quiescence by repressing N-Myc and mediates IL-1beta-driven myeloid differentiation, such that its loss confers selective expansion under inflammatory stress; a myeloid-specific +42 kb enhancer that loops to the CEBPA promoter restricts this activity to the myeloid compartment (PMID:23502316, PMID:26966090, PMID:33914855). C/EBPalpha activity is tuned post-translationally—ERK1/2 phosphorylation at serine 21 inactivates it downstream of oncogenic FLT3 and blocks granulocytic differentiation, while sumoylation at K159 blocks SWI/SNF recruitment (PMID:16446383, PMID:18406180)—and its intrinsically disordered region drives aromatic-residue-dependent phase separation that organizes long-range chromatin hubs (PMID:37516962). C/EBPalpha also directly binds the long DNMT3A isoform and inhibits its methyltransferase activity, coupling the factor to genome methylation control (PMID:35080973). Recurrent AML mutations corrupt these functions: the N-terminally truncated p30 isoform co-opts the MLL1 complex to activate aberrant enhancers and targets including GATA2 and CD73, while the N321D mutation disrupts the DNMT3A interaction to cause hypermethylation of PRC2 targets (PMID:30679799, PMID:31309149, PMID:35080973).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1988 High

    Establishing that CEBPA encodes a single sequence-specific DNA-binding protein defined the molecular identity of the factor and localized its activity to a discrete domain.

    Evidence recombinant bacterial expression with in vitro DNA-binding and protease fragment mapping

    PMID:2850264

    Open questions at the time
    • No structure of the DNA-bound complex
    • Cellular partners and target genes not yet defined
  2. 1991 High

    Biophysical characterization showed the basic region is disordered until DNA binding induces a fully helical fork, explaining how specific recognition is achieved.

    Evidence circular dichroism and DNA-binding titration on intact bZip protein

    PMID:1892816

    Open questions at the time
    • Single biophysical method
    • Does not address dimer selectivity or partner-dependent binding in vivo
  3. 1991 High

    Temporal expression and heterodimerization data placed C/EBPalpha as a terminal effector in a differentiation cascade rather than an early inducer.

    Evidence Western/Northern blotting, heterodimerization and transactivation assays in adipocyte and hepatoma cells

    PMID:1840554

    Open questions at the time
    • Mechanism of cascade hand-off between C/EBP family members unresolved
    • In vivo physiological roles not yet tested
  4. 1995 High

    Germline knockout established C/EBPalpha as essential for energy homeostasis, linking the transcription factor to specific metabolic gene programs in liver and fat.

    Evidence homozygous null mice with Northern and histological phenotyping

    PMID:7652557

    Open questions at the time
    • Neonatal lethality precludes adult analysis
    • Direct vs indirect target genes not separated
  5. 1997 High

    Adult liver-specific conditional deletion separated developmental requirement from ongoing transcriptional control, identifying discrete target genes regulated in mature hepatocytes.

    Evidence Cre/loxP conditional KO with Northern and biochemical phenotyping

    PMID:9315660

    Open questions at the time
    • Mechanism of target-gene selectivity unknown
    • Cofactor requirements not defined
  6. 1996 High

    Demonstrating cooperative activation with c-Myb and PU.1 revealed C/EBPalpha works combinatorially at myeloid promoters, likely via a bridging coactivator.

    Evidence reporter assays with binding-site mutagenesis and EMSA across multiple cell lines

    PMID:8756629

    Open questions at the time
    • Identity of the bridging coactivator not established
    • Direct vs indirect cooperativity not resolved
  7. 1998 High

    Separating lineage commitment (transactivation-independent) from maturation (transactivation-dependent) showed C/EBP function is modular in hematopoietic fate decisions.

    Evidence retroviral forced expression and dominant-negative alleles in multipotent progenitors

    PMID:9694805

    Open questions at the time
    • Transactivation-independent commitment mechanism undefined
    • Overlap with C/EBPbeta function not fully separated
  8. 2001 Medium

    Identifying RB as a direct binding partner that activates C/EBP-dependent transcription linked C/EBP factors to a cell-cycle regulator at target promoters.

    Evidence reciprocal Co-IP, GST pulldown, EMSA and reporter assays with RB domain mapping

    PMID:11596110

    Open questions at the time
    • Single lab
    • Physiological relevance in vivo not established
  9. 2006 High

    Pinpointing ERK1/2 phosphorylation of serine 21 as a functional off-switch explained how oncogenic FLT3 signaling blocks granulocytic differentiation.

    Evidence S21A/S21D mutagenesis with stable expression and kinase-inhibitor differentiation assays in AML cells

    PMID:16446383

    Open questions at the time
    • Structural consequence of S21 phosphorylation unknown
    • Whether phosphorylation alters DNA binding vs cofactor recruitment unresolved
  10. 2008 Medium

    Sumoylation at K159 was identified as a modification that blocks SWI/SNF recruitment, defining a chromatin-remodeling control point on C/EBPalpha.

    Evidence SUMO modification and Co-IP of SWI/SNF with C/EBPalpha mutants (review citing primary data)

    PMID:18406180

    Open questions at the time
    • Primary experiments cited rather than fully described
    • SUMO E3 ligase and dynamics not defined
  11. 2008 High

    Genome-wide co-localization with PPARgamma established that C/EBPalpha cooperatively orchestrates the adipocyte gene program through adjacent binding.

    Evidence ChIP-chip in 3T3-L1 adipocytes with motif analysis and loss-of-function

    PMID:18981473

    Open questions at the time
    • Order of recruitment between PPARgamma and C/EBPalpha not resolved
    • Direct physical interaction at shared sites not shown
  12. 2011 High

    PU.1/C/EBPalpha synergy in creating monocyte-specific enhancers showed C/EBPalpha determines cell-type-specific NF-kappaB genomic targeting.

    Evidence ChIP-seq, histone profiling and ectopic PU.1/C/EBPalpha expression in non-myeloid cells

    PMID:21402921

    Open questions at the time
    • Mechanism of de novo enhancer establishment not detailed
    • Direct C/EBPalpha-PU.1 contact not demonstrated
  13. 2013 High

    Inducible HSC knockout identified C/EBPalpha as a controller of adult HSC quiescence acting through direct repression of N-Myc.

    Evidence inducible conditional KO with transcriptional profiling and ChIP target validation

    PMID:23502316

    Open questions at the time
    • How C/EBPalpha represses N-Myc mechanistically not defined
    • Cofactors of repression unknown
  14. 2015 Medium

    Positioning CEBPA downstream of a p53-KLF4 axis provided a transcriptional input controlling its expression and a route to restore differentiation in AML.

    Evidence CEBPA-promoter reporter assays with p53/KLF4, patient-sample correlation, pharmacological p53 restoration

    PMID:26408402

    Open questions at the time
    • Promoter activation shown only by co-transfection
    • Patient correlation is associative
  15. 2016 High

    A myeloid-specific +42 kb enhancer that loops to the promoter was shown to confer tissue-restricted CEBPA expression essential for granulopoiesis and HSC maintenance.

    Evidence in vivo CRISPR enhancer deletion with 3C/4C, ChIP and phenotyping

    PMID:26966090

    Open questions at the time
    • Trans-factors binding the enhancer not fully cataloged
    • Mechanism of looping not defined
  16. 2017 High

    Identifying CEBPA mRNA as a target of the FTO/m6A axis revealed post-transcriptional control of its abundance in leukemia.

    Evidence FTO inhibition assay, m6A-seq, mRNA stability assays in leukemia models

    PMID:29249359

    Open questions at the time
    • m6A reader mediating CEBPA decay not identified here
    • Site-specific m6A marks on CEBPA not mapped
  17. 2019 High

    The oncogenic p30 isoform was shown to physically co-opt the MLL1 complex to activate aberrant targets such as GATA2, defining a gain-of-function leukemogenic mechanism.

    Evidence reciprocal Co-IP, ChIP-seq, CRISPR and pharmacological MLL1 perturbation

    PMID:30679799

    Open questions at the time
    • Structural basis of p30-MLL1 interaction unknown
    • Why full-length C/EBPalpha does not recruit MLL1 not resolved
  18. 2019 High

    Mapping p30-specific aberrant enhancers to CD73 connected a CEBPA driver mutation to a druggable downstream adenosine axis.

    Evidence in vivo ChIP-seq, chromatin conformation capture, cross-species expression and pharmacological targeting

    PMID:31309149

    Open questions at the time
    • Determinants of p30 enhancer selectivity not defined
    • Generality across CEBPA-mutant AML subtypes unclear
  19. 2021 High

    Competitive transplantation revealed C/EBPalpha as the effector of IL-1beta-driven myeloid differentiation, explaining selective expansion of Cebpa-mutant clones under chronic inflammation.

    Evidence inducible conditional KO with competitive transplantation, profiling and human AML validation

    PMID:33914855

    Open questions at the time
    • Direct IL-1beta-to-CEBPA signaling intermediates not mapped
    • Whether effect is shared with other inflammatory cytokines untested
  20. 2021 High

    Demonstrating high-affinity binding of CEBP sites to T:G mismatches that blocks glycosylase repair provided a mechanism linking factor occupancy to somatic C-to-T mutation.

    Evidence in vitro binding affinity and glycosylase repair-inhibition assays with somatic mutation enrichment analysis

    PMID:33877329

    Open questions at the time
    • Shown for CEBPbeta; CEBPA-specific contribution not isolated
    • In vivo mutagenesis at CEBPA-bound sites not demonstrated
  21. 2020 High

    Placing C/EBPalpha downstream of JAM-A signaling and upstream of claudin-5 transcription extended its role to endothelial barrier function.

    Evidence JAM-A KO mice, ChIP at claudin-5 promoter, reciprocal gain/loss-of-function and permeability assays

    PMID:32673519

    Open questions at the time
    • How JAM-A/EPAC signaling reaches CEBPA not detailed
    • Cofactors at the claudin-5 promoter unknown
  22. 2022 High

    Direct inhibition of DNMT3A methyltransferase activity by CEBPA, disrupted by the AML N321D mutation, established CEBPA as a guardian against aberrant DNA methylation.

    Evidence Co-IP with DNMT3A isoforms, in vitro methyltransferase assay, bisulfite profiling and N321D mutagenesis

    PMID:35080973

    Open questions at the time
    • Structural basis of CEBPA-DNMT3A N-terminus contact unknown
    • Genomic targeting of the inhibitory effect not fully resolved
  23. 2023 High

    Showing that the CEBPA IDR phase-separates and organizes long-range chromatin hubs added a biophysical layer to how the factor reshapes 3D genome architecture.

    Evidence in vitro phase separation with aromatic-residue mutagenesis, Hi-C, live imaging and ChIP-seq during transdifferentiation

    PMID:37516962

    Open questions at the time
    • Functional requirement of phase separation for target activation not isolated
    • Whether condensates form at endogenous physiological concentrations unresolved
  24. 2024 High

    Conditional deletion in lung showed CEBPA restricts alveolar type 2 cell plasticity by recruiting NKX2-1 and suppressing a SOX9 progenitor program.

    Evidence neonatal and adult conditional KO, viral infection model, scRNA-seq and cofactor recruitment assays

    PMID:38755149

    Open questions at the time
    • Mechanism of NKX2-1 recruitment not detailed
    • How injury overrides CEBPA restriction unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the combinatorial logic—dimer partner choice, IDR-driven condensates, post-translational marks, and DNMT3A control—is integrated to select context-specific target genes remains unresolved.
  • No unified structural model of partner-dependent target selection
  • Relationship between phase separation and post-translational modification states untested
  • Quantitative link between condensate formation and transcriptional output missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3
Partners
C-MYBCEBPBDNMT3AMLL1NKX2-1PPARGPU.1RB1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 C/EBP (CEBPA) was cloned and shown to encode a single protein with dual DNA-binding activities: selective binding to the CCAAT homology of viral promoters and to the enhancer core homology. The DNA-binding domain was localized to a 14-kD fragment by protease mapping, and a 60-amino-acid segment within it bears sequence similarity to myc and fos oncogenes. Recombinant bacterial expression, in vitro DNA-binding assay, protease fragment analysis, sequence analysis Genes & development High 2850264
1991 C/EBP alpha (CEBPA) protein is expressed only during the late phase of adipocyte differentiation in 3T3-L1 cells, in contrast to C/EBP beta and delta which peak early. C/EBP beta and delta form heterodimers with C/EBP alpha, and they activate transcription from the serum albumin gene promoter in hepatoma cells. This temporal expression pattern suggests a regulatory cascade controlling terminal differentiation. Western blotting, Northern blotting, transient transfection/reporter assay, heterodimerization analysis Genes & development High 1840554
1991 In the absence of specific DNA, the basic region of C/EBP bZip fragment is flexible and partially disordered; binding to a specific DNA recognition sequence induces a fully alpha-helical conformation in the basic region ('induced helical fork model'). This was demonstrated for the intact bZip protein of C/EBP. Circular dichroism (CD) spectroscopy, DNA-binding titration with symmetric and asymmetric enhancers Biochemistry High 1892816
1995 Homozygous deletion of c/ebp alpha in mice results in failure to store hepatic glycogen, hypoglycemia, and neonatal death. Mutant livers show 50-70% reduced glycogen synthase mRNA and delayed transcriptional induction of gluconeogenic enzymes PEPCK and glucose-6-phosphatase. Hepatocytes and adipocytes fail to accumulate lipid, and uncoupling protein expression is reduced in brown adipose tissue, establishing C/EBPα as critical for energy homeostasis. Targeted gene knockout (homozygous null mice), Northern blotting, histology Science High 7652557
1996 C/EBPα, c-Myb, and PU.1 cooperatively activate the neutrophil elastase (NE) promoter through their respective binding sites at -57, -49, and -82. Cooperative activation was observed with any combination of these factors. Either of C/EBPα's two transactivation domains cooperated with c-Myb, suggesting a coactivator protein bridges their interaction rather than direct protein-protein contact. Spatial separation of binding sites did not abolish cooperativity. Transient transfection/reporter assay (NIH 3T3, CV-1, 32D cl3 cells), gel shift/EMSA, site-directed mutagenesis of binding sites Molecular and cellular biology High 8756629
1997 Conditional deletion of c/ebp alpha specifically in adult mouse liver (via Cre/loxP) reduced expression of bilirubin UDP-glucuronosyltransferase, causing severe jaundice due to increased unconjugated bilirubin. Expression of PEPCK, glycogen synthase, and factor IX was strongly reduced, while transferrin, apoB, and IGF-I were unaffected, establishing C/EBPα as an essential transcriptional regulator of specific metabolic genes in adult liver. Conditional knockout (Cre/loxP recombination via adenoviral Cre delivery), Northern blotting, biochemical phenotyping Molecular and cellular biology High 9315660
1998 C/EBP alpha and C/EBP beta can induce eosinophil lineage commitment in multipotent hematopoietic progenitors (MEPs). Eosinophil differentiation can be separated into lineage commitment (transactivation-independent C/EBP function) and maturation (transactivation-dependent). Transactivation-deficient C/EBPβ alleles allowed commitment but blocked maturation. Retroviral forced expression of C/EBP isoforms in MEPs, dominant-negative allele analysis, conditional C/EBPβ activation Genes & development High 9694805
2001 Retinoblastoma protein (RB) forms stable complexes with C/EBPα, C/EBPβ, and C/EBPδ. The RB small pocket domain (aa 379-792) is necessary and sufficient for interaction with C/EBP proteins. RB-C/EBP complexes directly bind C/EBP sites on DNA and activate C/EBP-dependent transcription of the surfactant protein D (SP-D) gene promoter. Co-immunoprecipitation, GST pulldown, EMSA, reporter/transient transfection assay, RB domain mutagenesis Journal of cellular biochemistry Medium 11596110
2003 C/EBPβ function is required for mitotic clonal expansion (MCE) during adipogenesis. A dominant-negative C/EBP (A-C/EBP) inhibited turnover of p27/Kip1, expression of cyclin A and CDK2, DNA replication, MCE, and subsequent adipogenesis. Mechanistically, A-C/EBP prevented nuclear import of C/EBPβ by obscuring its nuclear localization signal, blocking its normal punctate centromeric staining. Adenoviral A-C/EBP expression, immunofluorescence, BrdU/DNA replication assay, Western blotting Proceedings of the National Academy of Sciences High 14688407
2006 FLT3-activating mutations in AML inhibit C/EBPα function via ERK1/2-mediated phosphorylation of serine 21. Pharmacological inhibition of FLT3 or MEK1 restores granulocytic differentiation. Expression of phosphorylation-resistant C/EBPα (S21A) restores differentiation, whereas the phosphomimetic S21D mutant does not, establishing ERK1/2-mediated S21 phosphorylation as a functional inactivation mechanism. Site-directed mutagenesis (S21A, S21D), stable expression in MV4;11 cells, FLT3/MEK inhibitor treatment, differentiation assay The Journal of experimental medicine High 16446383
2008 Sumoylation of C/EBPα at lysine 159 (K159) prevents association of the SWI/SNF chromatin remodeling complex with C/EBPα, thereby hampering transactivation. K159 lies within the growth inhibitory region of C/EBPα. SUMO modification assay, Co-immunoprecipitation of SWI/SNF with C/EBPα mutants (review citing primary experimental data) Blood cells, molecules & diseases Medium 18406180
2008 Genome-wide ChIP analysis in 3T3-L1 adipocytes showed that C/EBPα co-localizes at 3350 of 5299 PPARγ-binding sites. Most genes induced in adipogenesis are bound by both PPARγ and C/EBPα, while very few are PPARγ-specific. C/EBPα and C/EBPβ are both required with PPARγ for robust adipocyte-specific gene expression, demonstrating cooperative orchestration of adipocyte biology through adjacent binding on a genome-wide scale. Chromatin immunoprecipitation coupled with whole-genome tiling arrays (ChIP-chip), bioinformatics motif analysis Genes & development High 18981473
2011 PU.1 and C/EBPα synergistically create monocyte-specific enhancers that direct NF-κB p65 to distinct genome locations upon TNF-α stimulation. Co-expression of PU.1 and C/EBPα in HeLa cells conferred TNF-α responsiveness to a subset of THP-1-specific NF-κB target genes, establishing C/EBPα as a determinant of cell-type-specific enhancer formation and NF-κB targeting. Genome-wide ChIP-seq, histone modification profiling, transient expression of PU.1 and C/EBPα in HeLa cells, NF-κB reporter assays Proceedings of the National Academy of Sciences High 21402921
2013 C/EBPα controls acquisition and maintenance of adult haematopoietic stem cell (HSC) quiescence. Inducible knockout of C/EBPα in adult HSCs caused pronounced increase in HSC number and enhanced proliferation, resembling fetal liver HSCs. N-Myc was identified as a direct downstream target: loss of C/EBPα caused de-repression of N-Myc, mechanistically linking C/EBPα to HSC cell-cycle control. Inducible Cre-mediated conditional knockout, transcription profiling, ChIP/target gene validation Nature cell biology High 23502316
2016 A single enhancer located +42 kb from CEBPA is active exclusively in myeloid cells and physically engages the CEBPA promoter. Germline deletion of this enhancer in mice specifically reduced Cebpa levels in HSCs and myeloid-primed progenitors, causing severe granulocytic differentiation defects and loss of HSC maintenance without affecting Cebpa expression in other tissues. CRISPR/Cas9 genome editing, chromosome conformation capture (3C/4C), ChIP, in vivo mouse modeling Blood High 26966090
2017 R-2-hydroxyglutarate (R-2HG) inhibits FTO (fat mass and obesity-associated protein) activity, leading to increased global m6A RNA modification, which in turn decreases the stability of CEBPA (and MYC) transcripts, suppressing relevant pathways. This established CEBPA mRNA stability as a node regulated by the FTO/m6A axis. FTO enzymatic inhibition assay, m6A-seq, mRNA stability assay, ectopic expression, in vitro and in vivo leukemia models Cell High 29249359
2019 Oncogenic C/EBPα p30 isoform (from N-terminal AML mutations) physically interacts with the MLL1 histone methyltransferase complex and shows global co-localization on chromatin. CRISPR/Cas9 mutagenesis of MLL1 induces proliferation arrest and myeloid differentiation in p30-expressing cells. GATA2 was identified as a direct critical transcriptional target of the p30-MLL1 interaction. Co-immunoprecipitation, ChIP-seq, CRISPR/Cas9 MLL1 mutagenesis, pharmacological MLL1 inhibition, gene expression profiling Leukemia High 30679799
2019 Mutant CEBPA-p30 isoform activates aberrant enhancers not occupied by wild-type C/EBPα, including a leukemic enhancer upstream of Nt5e (CD73) that is physically and functionally linked to that gene. CD73 expression sustained leukemic growth via the CD73/A2AR axis, establishing a direct mechanistic link between a C/EBPα driver mutation and a druggable downstream target. Microscale in vivo ChIP-seq, chromatin conformation capture, comparative gene expression (human AML and mouse Cebpa-Lp30 model), reporter assay, pharmacological targeting Science advances High 31309149
2020 JAM-A promotes C/EBPα expression through suppression of β-catenin transcriptional activity and through activation of EPAC. C/EBPα then directly binds the promoter of claudin-5 to promote its transcription, enhancing endothelial barrier function. Genetic deletion of JAM-A reduced vascular permeability and claudin-5 levels; C/EBPα gain-of-function increased claudin-5 and decreased permeability; C/EBPα loss-of-function had the opposite effects. Genetic KO (JAM-A mice), ChIP on C/EBPα at claudin-5 promoter, gain/loss-of-function transfection, FITC-dextran permeability assay, pharmacological EPAC activation Circulation research High 32673519
2021 Chronic IL-1β exposure engendered potent selective expansion of Cebpa-knockout HSPCs in competitive settings. Cebpa loss did not confer cell-intrinsic competitive advantage under basal conditions. Mechanistically, C/EBPα mediates IL-1β-driven myeloid differentiation and repression of stem cell gene programs; Cebpa-KO HSPCs are resistant to the pro-differentiative effects of IL-1β, explaining their selective expansion. Competitive transplantation, inducible conditional knockout, gene expression profiling, ectopic CEBPA expression in human AML cells The Journal of experimental medicine High 33914855
2022 CEBPA directly interacts with the long isoform DNMT3A (but not DNMT3A2). By interacting with the DNMT3A N-terminus, CEBPA blocks DNMT3A from accessing DNA substrate and thereby inhibits its methyltransferase activity. Recurrent AML-associated CEBPA mutation N321D disrupts DNMT3A association and causes aberrant DNA hypermethylation of PRC2 target genes. Co-immunoprecipitation (CEBPA with DNMT3A isoforms), in vitro DNA methyltransferase activity assay, bisulfite sequencing/methylation profiling, site-directed mutagenesis (N321D) Science advances High 35080973
2023 CEBPA drives extensive chromatin compartment switching and formation of long-range chromatin hubs during B cell-to-macrophage transdifferentiation. The intrinsically disordered region (IDR) of CEBPA undergoes phase separation in vitro dependent on aromatic residues, and CEBPA forms nuclear foci in vivo in multiple cell types. This suggests phase separation through the IDR underlies CEBPA foci formation and 3D chromatin hub organization. Hi-C/chromatin conformation analysis, in vitro phase separation assay with purified CEBPA IDR, mutagenesis of aromatic residues, live-cell imaging of nuclear foci, ChIP-seq Cell reports High 37516962
2024 CEBPA restricts alveolar type 2 (AT2) cell plasticity in the mouse lung. Without CEBPA, neonatal AT2 cells reactivate the SOX9 progenitor program (mature AT2 cells cannot). Sendai virus infection bestows mature AT2 cells with neonatal plasticity in a Cebpa-mutant-dependent manner. Mechanistically, CEBPA promotes the AT2 program by recruiting the lineage TF NKX2-1. Conditional knockout (neonatal and adult), viral infection model, scRNA-seq/transcriptome profiling, ChIP/co-factor recruitment assay Nature communications High 38755149
2021 CEBPβ preferentially binds T:G mismatches (product of 5mC deamination) with >60-fold increased affinity relative to normal C:G base pairs within a CEBP binding site. This enhanced mismatch binding inhibits repair by TDG and MBD4 in vitro, as well as repair of U:G mismatches, providing a mechanism by which CEBP site occupancy drives C-to-T somatic mutations. In vitro binding affinity assay (fluorescence anisotropy/EMSAs), in vitro DNA glycosylase repair inhibition assay, somatic mutation enrichment analysis Nucleic acids research High 33877329
2015 The p53-KLF4-CEBPA axis is functionally connected: CEBPA gene transcription can be directly activated by p53 and KLF4. In AML patient cells, p53 inactivation correlates with reduced KLF4 and CEBPA protein levels. Restoring p53 function with chemotherapy or non-genotoxic p53 activators induces CEBPA gene expression and myeloid differentiation in AML cell lines. Reporter assay (CEBPA promoter with p53/KLF4 co-expression), protein level analysis in patient samples, pharmacological p53 restoration Clinical cancer research Medium 26408402

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes & development 1514 1840554
1988 Isolation of a recombinant copy of the gene encoding C/EBP. Genes & development 927 2850264
2017 R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling. Cell 917 29249359
1995 Impaired energy homeostasis in C/EBP alpha knockout mice. Science (New York, N.Y.) 816 7652557
2008 PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes & development 693 18981473
1999 A C/EBP beta isoform recruits the SWI/SNF complex to activate myeloid genes. Molecular cell 276 10619021
2005 Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. Journal of cell science 237 15944395
1995 The C/EBP family of transcription factors. Immunobiology 221 8530141
1996 C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter. Molecular and cellular biology 209 8756629
2013 C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. The EMBO journal 190 23665916
2012 C/EBP transcription factors mediate epicardial activation during heart development and injury. Science (New York, N.Y.) 188 23160954
2006 Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. The Journal of experimental medicine 172 16446383
1997 Disruption of the c/ebp alpha gene in adult mouse liver. Molecular and cellular biology 161 9315660
1994 C/EBP beta regulation of the tumor necrosis factor alpha gene. The Journal of clinical investigation 161 7929820
2003 Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes. Proceedings of the National Academy of Sciences of the United States of America 157 14688407
2001 Altered expression of C/EBP family members results in decreased adipogenesis with aging. American journal of physiology. Regulatory, integrative and comparative physiology 146 11353682
2005 CEBPA point mutations in hematological malignancies. Leukemia 140 15674366
2005 Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Blood 127 15985538
1998 Transcription factors C/EBP alpha, C/EBP beta, and CHOP (Gadd153) expressed during the differentiation program of keratinocytes in vitro and in vivo. The Journal of investigative dermatology 123 9506442
2018 PIWIL3/OIP5-AS1/miR-367-3p/CEBPA feedback loop regulates the biological behavior of glioma cells. Theranostics 121 29464001
2013 C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nature cell biology 120 23502316
2022 CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome. Blood 117 34320176
1991 DNA-induced increase in the alpha-helical content of C/EBP and GCN4. Biochemistry 114 1892816
1995 C/EBP alpha: a critical regulator of genes governing integrative metabolic processes. Current opinion in genetics & development 109 8664543
2020 JAM-A Acts via C/EBP-α to Promote Claudin-5 Expression and Enhance Endothelial Barrier Function. Circulation research 106 32673519
1998 The C/EBP family of transcription factors in the liver and other organs. International journal of experimental pathology 104 10319019
1998 Distinct C/EBP functions are required for eosinophil lineage commitment and maturation. Genes & development 92 9694805
2009 Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 91 19706798
2003 C/EBP transcription factors in the lung epithelium. American journal of physiology. Lung cellular and molecular physiology 83 12959923
2013 C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. The Journal of biological chemistry 76 23720735
2020 Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA). Blood 74 32430494
2002 C/EBP DNA-binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle. American journal of physiology. Regulatory, integrative and comparative physiology 74 11792653
2016 An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. Blood 73 26966090
2011 PU.1 and C/EBP(alpha) synergistically program distinct response to NF-kappaB activation through establishing monocyte specific enhancers. Proceedings of the National Academy of Sciences of the United States of America 67 21402921
2013 C/EBP homologous protein drives pro-catabolic responses in chondrocytes. Arthritis research & therapy 62 24351550
2000 Sp1 and C/EBP are necessary to activate the lactoferrin gene promoter during myeloid differentiation. Blood 60 10845904
2018 Apigetrin inhibits adipogenesis in 3T3-L1 cells by downregulating PPARγ and CEBP-α. Lipids in health and disease 59 29695233
2006 Expression and function of C/EBP homology protein (GADD153) in podocytes. The American journal of pathology 55 16400006
2021 Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors. The Journal of experimental medicine 52 33914855
2020 STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway. Oncogene 52 33323974
2003 Subnuclear localization of C/EBP beta is regulated by growth hormone and dependent on MAPK. The Journal of biological chemistry 52 12821655
2001 Molecular cloning, genetic mapping, and expression analysis of four zebrafish c/ebp genes. Gene 50 11750126
2017 A Bach2-Cebp Gene Regulatory Network for the Commitment of Multipotent Hematopoietic Progenitors. Cell reports 49 28273455
2017 Familial CEBPA-mutated acute myeloid leukemia. Seminars in hematology 49 28637622
1998 STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production. International immunology 47 9796920
1996 Control of adipocyte differentiation by CCAAT/enhancer binding protein alpha (C/EBP alpha). International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 47 8680485
2022 LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/β-catenin activation via interacting with hnRNPC. Journal of experimental & clinical cancer research : CR 45 36471363
2015 Inactivation of the p53-KLF4-CEBPA Axis in Acute Myeloid Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 43 26408402
2012 Inhibition of CD200R1 expression by C/EBP β in reactive microglial cells. Journal of neuroinflammation 42 22776069
2001 Retinoblastoma protein complexes with C/EBP proteins and activates C/EBP-mediated transcription. Journal of cellular biochemistry 41 11596110
2019 Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML. Science advances 40 31309149
2015 DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish. Journal of hematology & oncology 40 25886310
2019 Estradiol stimulates adipogenesis and Slc2a4/GLUT4 expression via ESR1-mediated activation of CEBPA. Molecular and cellular endocrinology 39 31100494
2018 Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma. Current pharmaceutical biotechnology 38 29886828
2003 Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells. Oncogene 37 12970736
2020 Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila. eLife 36 31909714
2013 Reciprocal modulation of C/EBP-α and C/EBP-β by IL-13 in activated microglia prevents neuronal death. European journal of immunology 36 23881867
2013 Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. PloS one 35 23646198
2022 Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions. Frontiers in oncology 34 35178345
2020 CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance. British journal of haematology 34 32086816
2015 CEBPA methylation and mutation in myelodysplastic syndrome. Medical oncology (Northwood, London, England) 34 26025484
2004 Suppression of C/EBP alpha expression in biliary cell differentiation from hepatoblasts during mouse liver development. Journal of hepatology 34 15519652
2019 Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice. Molecular therapy : the journal of the American Society of Gene Therapy 33 30852139
2007 C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis. Biochemical and biophysical research communications 33 18166146
2006 C/EBP homologous protein is necessary for normal osteoblastic function. Journal of cellular biochemistry 33 16220546
1992 Characterization and developmental expression of Xenopus C/EBP gene. Mechanisms of development 32 1525039
2014 Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PloS one 31 25314137
2010 C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity. The Journal of biological chemistry 31 20829351
2022 Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity. Science advances 30 35080973
2014 CEBPA-dependent HK3 and KLF5 expression in primary AML and during AML differentiation. Scientific reports 29 24584857
2013 Ikaros limits basophil development by suppressing C/EBP-α expression. Blood 29 23990620
2012 Artemisinic acid is a regulator of adipocyte differentiation and C/EBP δ expression. Journal of cellular biochemistry 29 22396222
2009 C/EBP{alpha} is required for pulmonary cytoprotection during hyperoxia. American journal of physiology. Lung cellular and molecular physiology 29 19465518
2024 CEBPA restricts alveolar type 2 cell plasticity during development and injury-repair. Nature communications 28 38755149
2019 CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex. Leukemia 27 30679799
2021 METTL3/14 and IL-17 signaling contribute to CEBPA-DT enhanced oral cancer cisplatin resistance. Oral diseases 26 34807506
2019 lncRNA CEBPA-AS1 Overexpression Inhibits Proliferation and Migration and Stimulates Apoptosis of OS Cells via Notch Signaling. Molecular therapy. Nucleic acids 26 32160715
2018 Impaired DNA demethylation of C/EBP sites causes premature aging. Genes & development 26 29884649
2018 Foxp3 expression in induced regulatory T cells is stabilized by C/EBP in inflammatory environments. EMBO reports 25 30348891
2021 Allele-specific expression of GATA2 due to epigenetic dysregulation in CEBPA double-mutant AML. Blood 24 33831168
2019 Shikonin induces apoptosis and suppresses growth in keratinocytes via CEBP-δ upregulation. International immunopharmacology 24 31075711
2019 Gain-of-Function Effects of N-Terminal CEBPA Mutations in Acute Myeloid Leukemia. BioEssays : news and reviews in molecular, cellular and developmental biology 24 31867767
2008 Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBP alpha). Blood cells, molecules & diseases 24 18406180
2023 CEBPA phase separation links transcriptional activity and 3D chromatin hubs. Cell reports 23 37516962
2019 Companion gene mutations and their clinical significance in AML with double mutant CEBPA. Cancer gene therapy 23 31477806
2016 Role of C/EBP-α in Adriamycin-induced podocyte injury. Scientific reports 23 27644413
2010 C/EBP alpha expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis. Laboratory investigation; a journal of technical methods and pathology 23 20386538
2000 Regulation of Gadd45gamma expression by C/EBP. European journal of biochemistry 23 11012671
1998 The transcription factors c-myb and C/EBP alpha regulate the monocytic/myeloic gene MRP14. Immunobiology 22 9717674
2019 Targeted regulation of fibroblast state by CRISPR-mediated CEBPA expression. Respiratory research 21 31829168
2013 Methylation status of CEBPA gene promoter in chronic myeloid leukemia. Hematology (Amsterdam, Netherlands) 21 23541085
2009 Albumin mediates PPAR-gamma or C/EBP-alpha-induced phenotypic changes in pancreatic stellate cells. Biochemical and biophysical research communications 20 19932685
2008 The HIF-1 alpha-C/EBP alpha axis. Science signaling 20 18957690
2021 MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models. International journal of molecular sciences 19 34502076
2016 Crosstalk between C/EBP homologous protein (CHOP) and glucocorticoid receptor in lung cancer. Molecular and cellular endocrinology 19 27496643
2024 TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA. Nature communications 18 39375377
2012 Asthma and COPD - The C/EBP Connection. The open respiratory medicine journal 18 22715349
2021 Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations. Nucleic acids research 17 33877329
2008 PU.1 and CEBPA expression in acute myeloid leukemia. Leukemia research 16 18308386
2024 Oncofetal TRIM71 drives liver cancer carcinogenesis through remodeling CEBPA-mediated serine/glycine metabolism. Theranostics 15 39267787

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