Affinage

NFIA

Nuclear factor 1 A-type · UniProt Q12857

Length
509 aa
Mass
55.9 kDa
Annotated
2026-06-10
93 papers in source corpus 32 papers cited in narrative 34 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

NFIA is a dimeric, sequence-specific transcription factor that acts as a context-dependent activator or repressor to control lineage commitment across the nervous system, blood, and adipose tissue (PMID:17178400, PMID:19542302, PMID:28812581). It recognizes a dyad-symmetric TGGCA(N3)TGCCA motif, and dimerization enhances both its DNA-binding affinity and specificity (PMID:41408833). In the developing CNS, NFIA is a master gliogenic switch: it is induced by Sox9 and forms a Sox9–NFIA protein complex to drive astrocyte gene programs, while repressing Notch effectors Hes1/Hes5 to terminate progenitor self-renewal and initiate differentiation (PMID:17178400, PMID:20610746, PMID:22500632); its activity depends on long-range enhancers regulated by Sox9 and Isl1-Lhx3 (PMID:28892058), and transient NFIA expression alone confers glial competency through reversible chromatin remodeling and GFAP promoter demethylation (PMID:30804533). Loss of NFIA in mice causes corpus callosum agenesis and hydrocephalus through failure of midline glia formation and commissural axon guidance, and a K125E loss-of-function variant impairs HES1 regulation and recapitulates these defects in model organisms (PMID:10518556, PMID:12514217, PMID:33973697). In adipocytes, NFIA binds brown-fat and beige enhancers ahead of PPARγ to increase chromatin accessibility and activate thermogenic and oxidative-phosphorylation genes, while directly repressing the inflammatory chemokine gene Ccl2 (PMID:28812581, PMID:37487068, PMID:35874098); a C-terminal pro#3 domain mediates this enhancer-penetrating activation, whereas a separate domain-independent mode lets NFIA repress Myod1 by competing with KLF5 (PMID:32991581). In hematopoiesis NFIA biases progenitor fate by activating beta-globin and repressing the G-CSF receptor (PMID:19542302), and in pancreatic progenitors it represses the E3 ligase Mib1 to restrain Dll1 endocytosis and Notch activation, promoting endocrine fate (PMID:30590051). NFIA also sustains immunosuppressive myeloid-derived suppressor cells during sepsis by repressing the cell-cycle inhibitor p21 (PMID:26259914, PMID:28167668). In disease, oncogenic NFIA fusions act through gain-of-function: NFIA-RAF1 drives constitutive RAF/MEK signaling from the plasma membrane (PMID:27810072), and NFIA-ETO2 represses erythroid genes and cooperates with mutant TP53 to drive erythroleukemia (PMID:36735909).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1999 High

    Established at the organismal level that NFIA is essential for forebrain development, defining a genetic requirement before its molecular targets were known.

    Evidence Nfia gene knockout in mice with histology and behavioral assessment

    PMID:10518556

    Open questions at the time
    • Did not identify direct transcriptional targets
    • Cellular basis of the corpus callosum phenotype unresolved at this stage
  2. 2003 High

    Resolved the cellular basis of the developmental phenotype by showing NFIA is required for midline glia formation and Slit2-dependent commissural axon guidance.

    Evidence Immunohistochemistry, in situ hybridization, axon tracing in Nfia knockout mice

    PMID:12514217

    Open questions at the time
    • Whether Slit2 is a direct NFIA target not established
    • Molecular mechanism of glial specification not yet defined
  3. 2004 High

    Identified NFIA biochemically as a sequence-specific transactivator and revealed isoform diversity, with a short splice variant lacking the transactivation domain acting as a dominant counter-regulator.

    Evidence DNA-affinity purification, mass spectrometry, reporter assays, and ChIP in rat olfactory mucosa

    PMID:15123731

    Open questions at the time
    • Physiological role of NFI-A-short isoform in vivo unknown
    • Tissue-specific promoter methylation control of NFIA targets not generalized
  4. 2005 High

    Defined a mechanistic role for NFIA in granulopoiesis through a competitive promoter switch with C/EBPalpha and a miR-223 negative-feedback loop, framing NFIA as a tunable lineage gatekeeper.

    Evidence Promoter competition, RNAi, ectopic expression, and translational reporters in APL cells

    PMID:16325577

    Open questions at the time
    • Did not address NFIA in erythroid fate
    • Structural basis of NFIA/C/EBPalpha competition not defined
  5. 2006 High

    Demonstrated NFIA is necessary and sufficient for gliogenesis onset, coupling glial gene activation to continued Notch-mediated repression of neurogenesis.

    Evidence In vivo knockout and gain-of-function electroporation in spinal cord progenitors

    PMID:17178400

    Open questions at the time
    • Upstream inducers of NFIA not yet identified
    • Direct vs indirect regulation of HES5 unresolved
  6. 2009 High

    Showed NFIA directly and oppositely regulates two lineage promoters (beta-globin activation, G-CSFR repression) to redirect hematopoietic progenitor fate, establishing dual activator/repressor function on direct targets.

    Evidence ChIP, reporter assays, gain/loss-of-function in hematopoietic progenitor cultures

    PMID:19542302

    Open questions at the time
    • Cofactors determining activation vs repression not identified
    • Chromatin context dictating bivalent behavior unknown
  7. 2010 High

    Unified NFIA's dual activity by showing it represses Hes1 to block self-renewal while activating astrocyte genes, linking the two arms of differentiation control.

    Evidence Nfia knockout mice, promoter reporters, and ChIP in telencephalic progenitors

    PMID:20610746

    Open questions at the time
    • Mechanism distinguishing repressive vs activating complexes not defined
  8. 2012 High

    Placed NFIA in a Sox9→NFIA cascade and demonstrated direct Sox9–NFIA complex formation co-regulating glial migration and metabolic genes.

    Evidence Co-IP, ChIP-seq, in vivo electroporation, and mouse genetics

    PMID:22500632

    Open questions at the time
    • Structural details of the Sox9-NFIA interface unknown
    • Genome-wide division of labor between Sox9 and NFIA incomplete
  9. 2015 Medium

    Extended NFIA's repressor role to innate immunity, showing it represses p21 to arrest myeloid differentiation and generate immunosuppressive MDSCs during sepsis.

    Evidence Gain/loss-of-function and ex vivo differentiation in septic mouse myeloid cells

    PMID:26259914

    Open questions at the time
    • Single-lab functional data without in vivo conditional deletion at this stage
    • Direct ChIP at p21 promoter not shown here
  10. 2017 High

    Established NFIA as a pioneer-like factor in brown fat that binds enhancers ahead of PPARγ to open chromatin and activate the thermogenic program, demonstrating a chromatin-priming mechanism.

    Evidence ATAC-seq, ChIP-seq, knockout mice, and myoblast overexpression

    PMID:28812581

    Open questions at the time
    • Whether NFIA binds nucleosomal DNA as a bona fide pioneer factor not directly tested
    • Cofactors recruited to open enhancers undefined
  11. 2017 High

    Confirmed and mechanistically anchored the MDSC role with myeloid-specific conditional deletion and a NFIA–miR-21/miR-181b regulatory loop sustaining immunosuppression.

    Evidence LysM-Cre × Nfia-flox conditional knockout, rescue, and CLP sepsis model

    PMID:28167668

    Open questions at the time
    • Direct microRNA-NFIA promoter interactions not fully mapped
  12. 2017 High

    Revealed lineage-specific long-range enhancer architecture controlling NFIA expression in glia versus neurons, and showed glioma exploits the glial enhancer configuration.

    Evidence In vivo enhancer reporters, chromatin conformation capture, enhancer deletion, glioma mouse models

    PMID:28892058

    Open questions at the time
    • How Sox9 vs Isl1-Lhx3 select distinct enhancers not resolved
  13. 2017 Medium

    Identified an NFIA-driven feed-forward NFκB loop conferring anti-apoptotic survival in glioblastoma, expanding NFIA into a pro-tumor transcriptional circuit.

    Evidence Knockdown/overexpression, apoptosis assays, and NFκB inhibitor epistasis in patient-derived GBM cells

    PMID:27994064

    Open questions at the time
    • Whether NFIA binds the p65 promoter directly not shown
    • Single-lab study
  14. 2018 High

    Defined a non-cell-autonomous Notch control mechanism whereby NFIA represses Mib1 to limit Dll1 endocytosis and promote pancreatic endocrine fate, with genetic rescue establishing causality.

    Evidence Pancreas-specific knockout, human progenitor gain-of-function, ChIP, and Mib1-knockdown epistasis

    PMID:30590051

    Open questions at the time
    • Cofactors mediating Mib1 repression not identified
  15. 2019 High

    Demonstrated NFIA is sufficient to confer human glial competency via rapid reversible chromatin remodeling, GFAP demethylation, and G1 lengthening, linking cell-cycle state to epigenetic licensing.

    Evidence Lentiviral NFIA in human PSC-derived NSCs, ATAC-seq, bisulfite sequencing, cell-cycle and pharmacological assays

    PMID:30804533

    Open questions at the time
    • Causal chain between G1 lengthening and chromatin opening incompletely separated
    • How NFIA directs demethylation machinery unknown
  16. 2020 High

    Mapped distinct domains for NFIA's opposing activities: a C-terminal pro#3 domain for enhancer-penetrating activation of Pparg, and a domain-independent KLF5-competitive mechanism for Myod1 repression.

    Evidence Deletion mutagenesis, ChIP-seq, and knockout rescue in adipogenic cells

    PMID:32991581

    Open questions at the time
    • Structural basis of chromatin penetration by pro#3 domain unknown
  17. 2021 Medium

    Showed NFIA forms heterodimers with NFIB in cortex and acts additively, indicating combinatorial NFI control of shared targets.

    Evidence Co-IP, compound knockout genetics, RNA-seq, ChIP-seq

    PMID:32166136

    Open questions at the time
    • Functional consequences of heterodimer vs homodimer not separated
    • Single-lab data
  18. 2021 Medium

    Identified Sox8 as a direct NFIA target that amplifies astrocytic differentiation through STAT3/p300, extending the gliogenic cascade downstream of NFIA.

    Evidence ChIP, Sox8 knockdown, Co-IP of Sox8 with STAT3/p300, methylation analysis

    PMID:34677001

    Open questions at the time
    • Single-lab study
    • Relative contribution of Sox8 vs other targets to gliogenesis unquantified
  19. 2021 Medium

    Linked NFIA to astrocyte physiology by showing it directly regulates TRPV4 to control astrocytic calcium activity and seizure susceptibility.

    Evidence In vivo RNAi/overexpression, ChIP, calcium imaging, EEG in a 4-AP epilepsy model

    PMID:37880726

    Open questions at the time
    • Single-lab study
    • Whether the effect is purely transcriptional not fully isolated
  20. 2022 High

    Established NFIA K125E as a disease-causing loss-of-function allele through cross-species rescue failure and impaired HES1 regulation, connecting NFIA dysfunction to human developmental disease.

    Evidence Drosophila ectopic expression, zebrafish morphant rescue, HES1 luciferase reporter

    PMID:33973697

    Open questions at the time
    • Full spectrum of patient phenotypes not mechanistically mapped
    • Structural impact of K125E on DNA binding not resolved here
  21. 2022 High

    Provided causal evidence that allele-specific NFIA binding at a Ucp1 enhancer SNP controls enhancer-promoter looping and thermogenic gene expression, demonstrating NFIA's role in 3D enhancer regulation.

    Evidence Allele-specific ChIP, chromatin conformation, CRISPR SNP editing in beige adipocytes

    PMID:35874098

    Open questions at the time
    • Looping machinery recruited by NFIA not identified
  22. 2023 High

    Defined the NFIA-ETO2 fusion oncomechanism, showing it redirects transcription from GATA to ETS targets and cooperates with mutant TP53 to drive pure erythroleukemia.

    Evidence Murine erythroblast expression, ChIP-seq, RNA-seq, transplantation, TP53 epistasis

    PMID:36735909

    Open questions at the time
    • Whether the fusion's repressive activity requires native NFIA partners unclear
  23. 2023 High

    Showed NFIA improves metabolic homeostasis in adipose tissue by facilitating PPARγ-driven oxidative phosphorylation genes and directly repressing the inflammatory chemokine Ccl2.

    Evidence Adipocyte-specific transgenic mice, ChIP-seq, glucose tolerance tests

    PMID:37487068

    Open questions at the time
    • Cofactors mediating Ccl2 repression not identified
  24. 2023 High

    Revealed a selective cell-type requirement for NFIA in retinal AII amacrine cell generation, with dependent loss of interconnected bipolar cells and impaired retinal physiology.

    Evidence Temporally controlled conditional knockout, cell counting, ERG

    PMID:37775301

    Open questions at the time
    • Direct retinal NFIA targets not identified
  25. 2025 High

    Provided the structural basis for NFI DNA recognition, showing dyad-symmetric motif binding and dimerization-enhanced affinity/specificity, and rationalizing how disease mutations impair DNA binding.

    Evidence X-ray crystallography of NFIA/NFIC-DNA complexes with mutagenesis and binding assays

    PMID:41408833

    Open questions at the time
    • Full-length NFIA structure with transactivation domains not determined
    • Structures with cofactors absent
  26. 2025 Medium

    Expanded NFIA into metabolic regulation in disease, showing it controls fatty acid metabolism in osteoarthritic chondrocytes and represses glycolysis/FN1 in pancreatic cancer.

    Evidence Multi-omics and NFIA inhibition in OA chondrocytes; ChIP and metabolic assays in pancreatic cancer cells

    PMID:40737429 PMID:41511661

    Open questions at the time
    • Context-dependent direction of metabolic regulation not reconciled
    • Single-lab studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NFIA's bidirectional activator/repressor output is selected at each locus — through specific cofactor recruitment, post-translational modification, and chromatin context — remains incompletely defined.
  • Cofactor partners that toggle NFIA between activation and repression unidentified
  • Role of post-translational modification (e.g. methylation) in activity switching unproven
  • Genome-wide rules predicting target outcome lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3
Partners
NFIBNFICPPARGSOX9

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 NFI-A (NFIA) competes with C/EBPalpha for binding to the miR-223 promoter: NFIA maintains miR-223 at low levels, whereas C/EBPalpha replaces NFIA upon retinoic acid-induced differentiation to upregulate miR-223 expression. Additionally, miR-223 represses NFIA translation, forming a negative-feedback loop that controls granulopoiesis. RNAi against NFIA and ectopic miR-223 both enhance granulocytic differentiation in APL cells. Promoter competition assay, RNAi knockdown, ectopic expression, translational reporter assays in APL cells Cell High 16325577
2006 NFIA is necessary and sufficient for induction of the glial marker GLAST in spinal cord ventricular zone progenitors, is required for continued inhibition of neurogenesis via HES5 (a Notch effector), and promotes migration and differentiation of astrocyte precursors. Loss of NFIA in the spinal cord prevents gliogenesis onset. In vivo loss-of-function (knockout mice), gain-of-function electroporation, immunofluorescence, gene expression analysis Neuron High 17178400
1999 Disruption of the murine Nfia gene causes agenesis of the corpus callosum and hydrocephalus, establishing NFIA as essential for corpus callosum formation and forebrain development. Gene knockout (homologous recombination), histology, behavioral assessment Proceedings of the National Academy of Sciences of the United States of America High 10518556
2003 NFIA is expressed in midline glial structures (glial wedge, indusium griseum, glial sling) of developing forebrain. In Nfia−/− mice, sling cells migrate aberrantly, midline glia are absent, Slit2 expression is reduced, and callosal axons fail to cross the midline, establishing NFIA as required for midline glia formation and commissural axon guidance. Immunohistochemistry, in situ hybridization, Nfia knockout mice, axon tracing The Journal of neuroscience High 12514217
2010 NFIA downregulates the Notch effector Hes1 in telencephalic progenitors, thereby repressing progenitor self-renewal while simultaneously activating astrocyte-specific gene expression. NFIA thus links repression of self-renewal to activation of differentiation. Loss-of-function in vivo (Nfia KO mice), promoter reporter assays, gene expression analysis, chromatin immunoprecipitation The Journal of neuroscience High 20610746
2012 Sox9 induces NFIA expression to initiate gliogenesis. Sox9 and NFIA then form a protein complex and co-regulate downstream glial genes including Apcdd1 (migration) and Mmd2 (metabolism). This defines a Sox9→NFIA transcriptional cascade for glial lineage commitment. Co-immunoprecipitation, ChIP-seq, in vivo electroporation, loss-of-function mouse genetics, gene expression analysis Neuron High 22500632
2009 NFIA directly binds and activates the beta-globin promoter while directly binding and repressing the G-CSF receptor promoter in hematopoietic progenitor cells, thereby directing progenitor fate toward the erythroid vs. granulocytic lineage. Chromatin immunoprecipitation, reporter assays, gain- and loss-of-function in unilineage and bilineage hematopoietic progenitor cultures Blood High 19542302
2017 NFIA co-localizes with PPARγ at brown-fat-specific enhancers; NFIA binding precedes and facilitates PPARγ binding, increasing chromatin accessibility and activating brown-fat gene transcription. NFIA-knockout brown fat shows impaired expression of brown-fat-specific genes and reciprocal elevation of muscle genes. Introduction of NFIA into myoblasts drives brown adipocyte differentiation. Genome-wide open chromatin analysis (ATAC-seq), ChIP-seq, NFIA knockout mice, lentiviral NFIA overexpression in myoblasts Nature cell biology High 28812581
2020 The C-terminal 17 amino acid residues of NFIA (pro#3 domain) are required for its transcriptional activity; this domain mediates chromatin penetration and binding to the Pparg enhancer to activate adipogenesis. Separately, a pro#3-domain-independent mechanism allows NFIA to bind the Myod1 enhancer and repress MyoD expression by competing with KLF5, suppressing the myogenic gene program. Deletion mutagenesis, ChIP-seq, NFIA-KO cell rescue experiments, reporter assays PLoS genetics High 32991581
2018 NFIA promotes endocrine cell fate in pancreatic progenitors by transcriptionally repressing Mib1 (an E3 ubiquitin ligase targeting Dll1 for endocytosis), thereby limiting Dll1 internalization and restraining Notch activation to allow neurogenin-3 expression. Pancreatic deletion of NFIA increases duct and decreases endocrine formation; Mib1 knockdown rescues the cell fate defects. Pancreas-specific NFIA knockout mice, ectopic NFIA expression in human pancreatic progenitors, ChIP for NFIA binding at Mib1 promoter, Dll1 endocytosis assay, epistasis (Mib1 KD rescue) Cell reports High 30590051
2023 NFIA in adipocytes upregulates oxidative phosphorylation genes by facilitating PPARγ genomic binding at enhancers and directly binds the regulatory region of the Ccl2 gene to repress MCP-1 transcription, thereby suppressing adipose tissue inflammation and improving glucose homeostasis. Adipocyte-specific NFIA transgenic mice, ChIP-seq, enhancer activation assays, glucose tolerance tests Proceedings of the National Academy of Sciences of the United States of America High 37487068
2015 During sepsis, NFIA transcriptionally represses the cyclin-dependent kinase inhibitor p21, arresting differentiation of Gr1+CD11b+ myeloid progenitors to generate immunosuppressive MDSCs. Knockdown of NFIA restores p21 expression and promotes monocyte/dendritic cell differentiation; ectopic NFIA in normal Gr1+CD11b+ cells generates an immunosuppressive phenotype. Gain- and loss-of-function (ectopic expression and siRNA knockdown), gene expression analysis, ex vivo differentiation assays in septic mouse myeloid cells Journal of leukocyte biology Medium 26259914
2017 Conditional myeloid-specific deletion of Nfia prevents MDSC expansion during sepsis; NFI-A-deficient Gr1+CD11b+ cells differentiate normally into macrophages and dendritic cells and are not immunosuppressive. Ectopic NFI-A expression in myeloid progenitors from Nfia-deficient mice restores MDSC phenotype. NFIA and miR-21/miR-181b form a mutual regulatory loop sustaining MDSC immunosuppression. Conditional myeloid knockout (LysM-Cre × Nfia-flox), ectopic NFI-A expression, ex vivo differentiation assays, cecal ligation and puncture sepsis model Infection and immunity High 28167668
2004 NFI-A proteins (identified via mass spectrometry after DNA-affinity purification from rat olfactory mucosa) bind the NPTA element in the CYP2A3 promoter and transactivate the gene in vitro. A novel alternative-splice isoform, NFI-A-short, lacks the transactivation domain and counteracts activation by full-length NFI-A2. ChIP demonstrates NFI association with the CYP2A3 promoter in olfactory mucosa but not in liver, where the promoter is hypermethylated. DNA-affinity purification, mass spectrometry, transient transfection reporter assay, chromatin immunoprecipitation (ChIP), alternative splicing analysis The Journal of biological chemistry High 15123731
2005 NFI-A1 activates transcription through the CEREM enhancer element of the UGT1A2 promoter; NFI-C1 has an inhibitory effect and suppresses NFI-A1-mediated activation in a concentration-dependent manner through heterodimerization competition at CEREM. Affinity chromatography, immunoblot with isoform-specific antibodies, co-expression reporter gene assay in cultured hepatocytes Journal of biochemistry Medium 16169882
2016 An NFIA:RAF1 fusion arising from chromosomal rearrangement results in constitutive Raf1 kinase activity, activates the MEK1/2 cascade, and promotes cancer cell proliferation. The NFIA:RAF1 fusion localizes to the plasma membrane (distinct from nuclear WT-NFIA and cytoplasmic WT-Raf1), indicating that NFIA sequences drive membrane targeting of the oncogenic fusion. RNA sequencing (fusion detection), kinase activity assay, MEK phosphorylation immunoblot, subcellular localization (immunofluorescence), cell proliferation assay Cancer genetics Medium 27810072
2017 NFIA activates NFκB p65 transcription and protein levels in glioblastoma cells; NFκB in turn activates the NFIA promoter, forming a feed-forward loop. NFIA-driven NFκB activation is required for upregulation of anti-apoptotic factors TRAF1 and cIAPs. NFIA knockdown decreases NFκB and increases baseline apoptosis; NFκB inhibition reverses the NFIA anti-apoptotic effect. Gain- and loss-of-function (knockdown/overexpression), gene expression analysis, apoptosis assays, epistasis by NFκB inhibitor rescue in patient-derived GBM cells Neuro-oncology Medium 27994064
2017 Sox9 and Isl1-Lhx3 regulate long-range enhancer activity to control NFIA expression in glial and neuronal populations in the spinal cord, respectively. These enhancers and transcription factors form distinct chromatin architectures (assessed by chromatin conformation analysis) in glial vs. neuronal lineages. In glioma models, the glia-specific chromatin architecture is preserved and these enhancers are required for NFIA expression and glioma formation. Enhancer reporter assays in vivo, chromatin conformation capture, genetic deletion of enhancers, glioma mouse models Nature neuroscience High 28892058
2021 NFIA directly regulates astrocytic TRPV4 expression; loss of NFIA inhibits TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, and suppresses seizure activity in a 4-AP epilepsy model. ChIP was used to identify NFIA binding at the TRPV4 regulatory region. RNAi knockdown of NFIA in vivo, NFIA overexpression (HA-tagged plasmid), ChIP for NFIA at TRPV4 promoter, calcium imaging, EEG seizure recording Journal of neuroinflammation Medium 37880726
2019 Transient NFIA expression is sufficient to trigger glial competency of human pluripotent stem cell-derived neural stem cells within 5 days, involving rapid but reversible chromatin remodeling, GFAP promoter demethylation, and lengthening of the G1 cell cycle phase. Genetic or pharmacological G1 length manipulation partially mimics NFIA function. Lentiviral NFIA overexpression in human PSC-derived NSCs, ATAC-seq, bisulfite sequencing, cell cycle analysis, pharmacological G1 manipulation Nature biotechnology High 30804533
2021 Sox8 is a direct transcriptional target of Nfia at the initiation of the gliogenic phase. Sox8 augments LIF-induced astrocytic differentiation by associating with STAT3 through transcriptional coactivator p300 (without inducing Gfap DNA demethylation, unlike Nfia itself). Sox8 knockdown inhibits Nfia-enhanced astrocytic differentiation. ChIP showing NFIA at Sox8 regulatory elements, Sox8 siRNA knockdown, Co-IP of Sox8 with STAT3 and p300, Gfap methylation analysis, differentiation assays Pharmacology research & perspectives Medium 34677001
2023 The NFIA-ETO2 fusion protein (from t(1;16)(p31;q24)) blocks erythroid differentiation by preferentially binding and repressing erythroid genes containing NFI binding sites and ETO2-decorated sites, shifting transcriptional activity from GATA- to ETS-motif-containing target genes. NFIA-ETO2 alone does not induce disease, but cooperates with TP53R248Q mutation to induce a fully penetrant transplantable pure erythroid leukemia in mice. Murine erythroblast retroviral expression, primary fetal liver EB cultures, transplantation assay, ChIP-seq, RNA-seq, motif analysis Blood High 36735909
2021 NFIA and NFIB are co-expressed in developing cortex and can form heterodimers in vivo (demonstrated by co-immunoprecipitation). Compound homozygous knockout of both genes produces a more severe cortical phenotype than single knockouts, indicating additive function. Shared differentially regulated target genes are enriched for NFI binding sites in their promoters. Co-immunoprecipitation, compound knockout mouse genetics, RNA-seq, ChIP-seq Brain and neuroscience advances Medium 32166136
2022 The NFIA missense variant K125E is a loss-of-function allele: ectopic wild-type NFIA in Drosophila causes developmental defects not seen with K125E-NFIA; wild-type human NFIA rescues commissural axon defects in nfia-deficient zebrafish but K125E does not; K125E impairs transcriptional regulation of the HES1 promoter in cultured cells. Drosophila ectopic expression assay, zebrafish nfia morphant rescue, HES1 promoter luciferase reporter assay American journal of medical genetics. Part A High 33973697
2025 Crystal structures of NFIC homodimer and NFIA/NFIC monomers lacking their dimerization region in complex with double-stranded DNA reveal that NFI proteins recognize a dyad-symmetric TGGCA(N3)TGCCA sequence motif. Dimerization enhances both DNA-binding affinity and specificity. Mutagenesis and binding assays validate key residues in protein-DNA interaction. Disease-associated mutations are shown to impair DNA binding. X-ray crystallography, mutagenesis, in vitro DNA-binding affinity assays (EMSA/ITC), structural analysis Acta biochimica et biophysica Sinica High 41408833
2025 In OA articular chondrocytes, NFIA upregulation drives increased fatty acid synthesis and oxidation by transcriptionally activating ACACA and CPT2. Inhibition of NFIA suppresses these metabolic enzymes and restores cellular homeostasis in murine and human OA chondrocytes. Multi-omics (RNA-seq, ATAC-seq, MRE-seq, metabolomics), NFIA inhibition in murine/human OA chondrocytes, gene expression analysis Science translational medicine Medium 40737429
2025 NFIA directly represses transcription of the glycolytic enzyme PKM in pancreatic cancer cells, thereby attenuating glycolysis. NFIA also transcriptionally suppresses FN1 expression. Loss of NFIA leads to increased glycolysis, histone lactylation, epigenetic upregulation of FN1, and activation of integrin α5β1-FAK-PI3K-Akt signaling. NFIA overexpression/knockdown, ChIP showing direct NFIA binding at PKM and FN1 promoters, glucose uptake/lactate assays, histone lactylation analysis, signaling pathway western blots Apoptosis Medium 41511661
2025 NFIA directly binds two motifs in the SMC4 promoter (-1379 bp and -354 bp) to drive SMC4 transcription in glioma cells, as validated by dual-luciferase and ChIP assays. SMC4 promotes metastasis via TGF-β/SMAD signaling and aerobic glycolysis via LDHA. Dual-luciferase reporter assay, ChIP assay for NFIA at SMC4 promoter, NFIA and SMC4 gain/loss-of-function in glioma cell lines, xenograft and tail-vein metastasis models Frontiers in oncology Medium 40933894
2025 NFIA represses S100A7 expression by directly binding the S100A7 promoter (validated by ChIP and dual-luciferase assay), reducing inflammation and apoptosis of keratinocytes in oral lichen planus. NFIA overexpression ameliorates OLP inflammation in vivo, an effect reversed by S100A7 overexpression. ChIP assay, dual-luciferase reporter assay, shRNA knockdown, in vivo OLP mouse model, ELISA, flow cytometry The Kaohsiung journal of medical sciences Medium 40560736
2022 NFIA determines allele-specific Ucp1 expression in beige adipocytes: the alternative T allele of rs47238345 at the Ucp1 -12kb enhancer in 129 mice facilitates allele-specific NFIA binding, which mediates allele-specific enhancer-promoter looping and Ucp1 transcription. CRISPR-mediated SNP editing of rs47238345 increases Ucp1 expression. Allele-specific ChIP, chromatin conformation assay (enhancer-promoter interaction), CRISPR-Cas9/Cpf1 SNP editing, allele-specific expression analysis iScience High 35874098
2023 In Nfia conditional knockout retinas, AII amacrine cells are massively and selectively absent. Type 2 cone bipolar cells (which are interconnected to AII cells) are also partially reduced, with their loss occurring after AII cell loss, indicating a dependency relationship. Nfia loss results in profound diminishment of oscillatory potentials in the ERG. Conditional knockout mice (Nfia-CKO), cell counting, ERG electrophysiology, temporal deletion (postnatal) The Journal of neuroscience High 37775301
2023 Astrocyte-derived extracellular vesicles (ADEVs) from obese/high-glucose-stimulated astrocytes are enriched in NFIA protein and are taken up by hippocampal neurons, causing synaptic injury and cognitive impairment. Astrocyte-specific knockdown of Nfia reduces NFIA in ADEVs and ameliorates synaptic dysfunction and cognitive impairment in obese mice. Proteomics of brain-derived EVs, AAV-mediated astrocyte-specific Nfia knockdown, ADEV isolation/administration, behavioral tests, synaptic protein analysis Journal of neuroinflammation Medium 40448146
2024 NFIA is required for motor neuron positioning, axonal branching, and neuromuscular junction formation in the spinal cord. NFIA is also required for proper mitochondrial function and ATP production in motor neurons, linking transcriptional regulation to metabolic function during motor circuit development. Conditional knockout mice, immunofluorescence, axon tracing, neuromuscular junction analysis, mitochondrial function assays (OCR/ATP production) bioRxivpreprint Medium
2025 CARM1 methylates NFIA (NFIA is a CARM1 substrate), and this CARM1/NFIA relationship represses NGFR signaling in glioma stem-like cells; loss of CARM1 dysregulates NFIA function and leads to increased NGFR/NTRK dependency. Multi-omics (proteomics + transcriptomics), CARM1 depletion, NFIA overexpression epistasis, NFIA-CARM1 substrate identification bioRxivpreprint Low

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell 822 16325577
2006 The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 401 17178400
2012 Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 292 22500632
1999 Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proceedings of the National Academy of Sciences of the United States of America 196 10518556
2019 NFIA is a gliogenic switch enabling rapid derivation of functional human astrocytes from pluripotent stem cells. Nature biotechnology 180 30804533
2003 Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 12514217
1990 Chicken NFI/TGGCA proteins are encoded by at least three independent genes: NFI-A, NFI-B and NFI-C with homologues in mammalian genomes. Nucleic acids research 172 2339052
2014 RP5-833A20.1/miR-382-5p/NFIA-dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis and inflammatory reaction. Arteriosclerosis, thrombosis, and vascular biology 163 25265644
2010 NFIA controls telencephalic progenitor cell differentiation through repression of the Notch effector Hes1. The Journal of neuroscience : the official journal of the Society for Neuroscience 123 20610746
2007 NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects. PLoS genetics 109 17530927
2014 MicroRNA 21 (miR-21) and miR-181b couple with NFI-A to generate myeloid-derived suppressor cells and promote immunosuppression in late sepsis. Infection and immunity 96 24980967
2017 NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program. Nature cell biology 87 28812581
1995 Chromosomal localization of the four genes (NFIA, B, C, and X) for the human transcription factor nuclear factor I by FISH. Genomics 72 7590749
2021 Macrophages-derived exosomal lncRNA LIFR-AS1 promotes osteosarcoma cell progression via miR-29a/NFIA axis. Cancer cell international 62 33794884
2021 Exosomal circEhmt1 Released from Hypoxia-Pretreated Pericytes Regulates High Glucose-Induced Microvascular Dysfunction via the NFIA/NLRP3 Pathway. Oxidative medicine and cellular longevity 57 33815662
2009 NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls beta-globin and G-CSF receptor expression. Blood 55 19542302
2020 MiRNA-671-5p Promotes prostate cancer development and metastasis by targeting NFIA/CRYAB axis. Cell death & disease 43 33144585
2017 Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis. Nature neuroscience 41 28892058
2014 An intragenic deletion of the NFIA gene in a patient with a hypoplastic corpus callosum, craniofacial abnormalities and urinary tract defects. European journal of medical genetics 37 24462883
2009 A novel 1p31.3p32.2 deletion involving the NFIA gene detected by array CGH in a patient with macrocephaly and hypoplasia of the corpus callosum. European journal of pediatrics 36 19763616
2016 A new NFIA:RAF1 fusion activating the MAPK pathway in pilocytic astrocytoma. Cancer genetics 32 27810072
2020 Common Regulatory Targets of NFIA, NFIX and NFIB during Postnatal Cerebellar Development. Cerebellum (London, England) 31 31838646
2017 A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival. Neuro-oncology 30 27994064
2011 Chromosome 1p32-p31 deletion syndrome: prenatal diagnosis by array comparative genomic hybridization using uncultured amniocytes and association with NFIA haploinsufficiency, ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and intrauterine growth restriction. Taiwanese journal of obstetrics & gynecology 29 22030051
2017 A novel pathway in NSCLC cells: miR‑191, targeting NFIA, is induced by chronic hypoxia, and promotes cell proliferation and migration. Molecular medicine reports 28 28075452
2015 Particulate β-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression. Oncoimmunology 28 26405609
2017 Combined allelic dosage of Nfia and Nfib regulates cortical development. Brain and neuroscience advances 27 32166136
2015 Truncating mutation in NFIA causes brain malformation and urinary tract defects. Human genome variation 27 27081522
2020 NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation. PLoS genetics 25 32991581
2023 NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis. Proceedings of the National Academy of Sciences of the United States of America 23 37487068
2021 SoxE group transcription factor Sox8 promotes astrocytic differentiation of neural stem/precursor cells downstream of Nfia. Pharmacology research & perspectives 22 34677001
2019 MiR-424 prevents astrogliosis after cerebral ischemia/reperfusion in elderly mice by enhancing repressive H3K27me3 via NFIA/DNMT1 signaling. The FEBS journal 22 31365782
2017 Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival. Infection and immunity 22 28167668
2020 LncRNA NFIA-AS2 promotes glioma progression through modulating the miR-655-3p/ZFX axis. Human cell 21 32779154
2021 LncRNA LINC00511 Acts as an Oncogene in Colorectal Cancer via Sponging miR-29c-3p to Upregulate NFIA. OncoTargets and therapy 20 33536761
2019 Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma. Journal of neuro-oncology 20 31760595
2017 Loss-of-function variants in NFIA provide further support that NFIA is a critical gene in 1p32-p31 deletion syndrome: A four patient series. American journal of medical genetics. Part A 20 28941020
2016 Long non-coding RNA RP5-833A20.1 inhibits proliferation, metastasis and cell cycle progression by suppressing the expression of NFIA in U251 cells. Molecular medicine reports 20 27779670
2015 NFI-A disrupts myeloid cell differentiation and maturation in septic mice. Journal of leukocyte biology 20 26259914
2016 Comparative deletion mapping at 1p31.3-p32.2 implies NFIA responsible for intellectual disability coupled with macrocephaly and the presence of several other genes for syndromic intellectual disability. Molecular cytogenetics 19 26997977
2014 miR-29a activates Hes1 by targeting Nfia in esophageal carcinoma cell line TE-1. Oncology letters 19 25435940
2004 Transcriptional regulation of rat CYP2A3 by nuclear factor 1: identification of a novel NFI-A isoform, and evidence for tissue-selective interaction of NFI with the CYP2A3 promoter in vivo. The Journal of biological chemistry 19 15123731
2017 Nfia deletion in myeloid cells blocks expansion of myeloid-derived suppressor cells during sepsis. Innate immunity 18 29172874
2023 Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity. Journal of neuroinflammation 17 37880726
2021 Novel t(1;8)(p31.3;q21.3) NFIA-RUNX1T1 Translocation in an Infant Erythroblastic Sarcoma. American journal of clinical pathology 17 33313700
2020 MALAT1 overexpression attenuates AS by inhibiting ox-LDL-stimulated dendritic cell maturation via miR-155-5p/NFIA axis. Cell cycle (Georgetown, Tex.) 17 32840181
2018 Pancreatic Cell Fate Determination Relies on Notch Ligand Trafficking by NFIA. Cell reports 16 30590051
2014 The nuclear factor I/A (NFIA) gene is associated with the asthma plus rhinitis phenotype. The Journal of allergy and clinical immunology 16 24560411
2021 Genome-wide association study identifies susceptibility loci of brain atrophy to NFIA and ST18 in Alzheimer's disease. Neurobiology of aging 14 33640202
2017 DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina. The Journal of comparative neurology 14 29071714
2021 NFIA and NFIB function as tumour suppressors in high-grade glioma in mice. Carcinogenesis 12 33346791
2023 SOX9/NFIA promotes human ovarian cancer metastasis through the Wnt/β-catenin signaling pathway. Pathology, research and practice 11 37315400
2021 Recurrent NFIA K125E substitution represents a loss-of-function allele: Sensitive in vitro and in vivo assays for nontruncating alleles. American journal of medical genetics. Part A 11 33973697
2015 PAX6 does not regulate Nfia and Nfib expression during neocortical development. Scientific reports 11 26021864
2015 TNF-α-mediated microRNA-136 induces differentiation of myeloid cells by targeting NFIA. Journal of leukocyte biology 11 26329426
2024 Association of ARRDC3 and NFIA variants with bovine congestive heart failure in feedlot cattle. F1000Research 10 38680232
2023 The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53. Blood 10 36735909
2019 A novel role for NFIA in restoring radiosensitivity in radioresistant NSCLC cells by downregulating the AKT and ERK pathways. Biochemical and biophysical research communications 10 31178144
2025 Aqueous extract of Rehmanniae Radix Praeparata improves bone health in ovariectomized rats by modulating the miR-29a-3p/NFIA/Wnt signaling pathway axis. Journal of ethnopharmacology 9 40024453
2020 A novel NFIA gene nonsense mutation in a Chinese patient with macrocephaly, corpus callosum hypoplasia, developmental delay, and dysmorphic features. Molecular genetics & genomic medicine 9 32926563
2020 HIF-1α and NFIA-AS2 Polymorphisms as Potential Determinants of Total Hemoglobin Mass in Endurance Athletes. Journal of strength and conditioning research 9 35622109
2005 Transcriptional enhancement of UDP-glucuronosyltransferase form 1A2 (UGT1A2) by nuclear factor I-A (NFI-A) in rat hepatocytes. Journal of biochemistry 9 16169882
2025 NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis. Science translational medicine 7 40737429
2022 miR-181d-5p Protects against Retinal Ganglion Cell Death after Blunt Ocular Injury by Regulating NFIA-Medicated Astrocyte Development. Mediators of inflammation 7 36254157
2022 An miRNA derived from amelogenin exon4 regulates expression of transcription factor Runx2 by directly targeting upstream activators Nfia and Prkch. The Journal of biological chemistry 6 35271849
2022 Phenotypic Spectrum of NFIA Haploinsufficiency: Two Additional Cases and Review of the Literature. Genes 6 36553517
2023 Inhibition of lncRNA NFIA-AS1 Alleviates Abnormal Proliferation and Inflammation of Vascular Smooth Muscle Cells in Atherosclerosis by Regulating miR-125a-3p/AKT1 Axis. International journal of genomics 5 37056786
2023 Nfia Is Critical for AII Amacrine Cell Production: Selective Bipolar Cell Dependencies and Diminished ERG. The Journal of neuroscience : the official journal of the Society for Neuroscience 5 37775301
2022 The p.Thr395Met missense variant of NFIA found in a patient with intellectual disability is a defective variant. American journal of medical genetics. Part A 5 35018717
2022 NFIA determines the cis-effect of genetic variation on Ucp1 expression in murine thermogenic adipocytes. iScience 5 35874098
2021 Direct Cell Reprogramming of Mouse Fibroblasts into Functional Astrocytes Using Lentiviral Overexpression of the Transcription Factors NFIA, NFIB, and SOX9. Methods in molecular biology (Clifton, N.J.) 5 34324178
2020 Expression of NFIA and NFIB within the murine spinal cord. Gene expression patterns : GEP 4 32068188
2025 Astrocyte-derived extracellular vesicular NFIA mediates obesity-associated cognitive impairment. Journal of neuroinflammation 3 40448146
2024 Significant phenotypic variability in a multigenerational family with an NFIA missense mutation: Case series and review of the literature. Clinical case reports 3 38188845
2024 CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions. Acta neuropathologica communications 3 38243303
2024 Generating iAstrocytes From Human Induced Pluripotent Stem Cells by Combining Low-Density Passaging of Neural Progenitor Cells and Transcription Factor NFIA Transdifferentiation. Current protocols 3 39546395
2022 Pathogenic variant in NFIA associated with subdural hematomas mimicking nonaccidental trauma. American journal of medical genetics. Part A 3 35006644
2025 Deletion of NFIA Leads to Activation of S100A7 and Inflammatory Response-Induced Apoptosis of Keratinocytes in Oral Lichen Planus Progression. The Kaohsiung journal of medical sciences 2 40560736
2025 Transcriptional control of brown adipocyte differentiation and function by NFIA: recent perspectives on deciphering metabolic diseases. Journal of biochemistry 2 40581369
2024 Pediatric Erythroid Sarcoma Diagnostically Confirmed by Identification of a Recurrent NFIA::CBFA2T3 Fusion. Genes, chromosomes & cancer 2 38884198
2023 Identification and characterization of the long non-coding RNA NFIA-AS2 as a novel locus for body mass index in American Indians. International journal of obesity (2005) 1 36806387
2020 Overseeing Memory Circuits by NFIA: New Face In Astrocytes. Neuron 1 32553203
2026 Downregulation of NFIA facilitates glycolysis, histone lactylation, and activation of the FN1-integrin α5β1 pathway in pancreatic cancer. Apoptosis : an international journal on programmed cell death 0 41511661
2026 Clinical significance and biological role of miR-592 in diabetic retinopathy via targeted negative regulation of NFIA. Experimental eye research 0 42036008
2026 The NFIA::CBFA2T3 identifies a molecularly defined subgroup of acute erythroid leukemia/erythroid sarcoma. Frontiers in oncology 0 42158426
2026 Identification of an NFIA::CBFA2T3 fusion in cerebrospinal fluid confirms the diagnosis of pediatric CNS myeloid sarcoma with erythroid differentiation: a case report and literature review. Frontiers in oncology 0 42205757
2025 A Case of Prenatal Diagnosis of NFIA -Related Disorder Indicated by Noninvasive Prenatal Testing. American journal of medical genetics. Part A 0 39996378
2025 Generation of human induced pluripotent stem cell lines derived from a patient carrying an intragenic deletion in the NFIA gene. Human cell 0 40266456
2025 Detection of a new heterozygous pathogenic NFIA variant in metopic craniosynostosis with preaxial polysyndactyly: A case report. JPRAS open 0 40606574
2025 NFIA-dependent upregulation of SMC4 promotes metastasis and metabolic reprogramming in glioma. Frontiers in oncology 0 40933894
2025 Biochemical and structural studies of NFIA and NFIC reveal a conserved mechanism for specific DNA recognition and provide insight into potential pathogenicity of disease-associated mutations. Acta biochimica et biophysica Sinica 0 41408833
2023 Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene. Open medicine (Warsaw, Poland) 0 37533740
2018 PAX6 can substitute for LHX2 and override NFIA-induced astrogliogenesis in developing hippocampus in vivo. Journal of biosciences 0 29485116

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