Affinage

DEAF1

Deformed epidermal autoregulatory factor 1 homolog · UniProt O75398

Length
565 aa
Mass
59.3 kDa
Annotated
2026-06-09
45 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DEAF1 (NUDR) is a sequence-specific transcription factor that controls programs in neurodevelopment, immune tolerance, innate immunity, serotonergic signaling, and muscle homeostasis (PMID:8617243, PMID:9773984, PMID:19668219, PMID:38963021). It recognizes unmethylated dual CpG-containing motifs built from repeated TTCGGG half-sites variably spaced 6–11 nt apart, and methylation of a single half-site abolishes binding (PMID:9773984, PMID:25531106). DNA recognition is conferred by the SAND domain region; the adjacent zinc-binding motif couples protein-protein interaction to DNA binding, and a CRM1-dependent nuclear export signal together with an NLS govern its nuclear-cytoplasmic distribution (PMID:15161925, PMID:28940898). A solved MYND domain adopts a ββα fold with cross-brace zinc sites that binds NCoR and SMRT corepressor peptides, providing the structural basis for transcriptional repression, which depends on histone deacetylation (PMID:23372760, PMID:16467535). DEAF1 acts as a cell-context-dependent repressor or activator: it represses the hnRNP A2/B1 promoter and its own promoter, represses the 5-HT1A autoreceptor in raphe neurons while enhancing it in non-serotonergic cells, and controls peripheral tissue antigen expression in lymph node stromal cells, where an alternatively spliced dominant-negative isoform (Deaf1-Var1) suppresses its activity (PMID:10521432, PMID:16467535, PMID:19668219, PMID:22232550). Through an intrinsically disordered region that becomes structured on binding LMO4 LIM domains, DEAF1 engages LMO4 as a competitive interaction hub that modulates its nuclear export (PMID:22723967, PMID:25310299). In innate immunity it binds the IFNβ promoter and interacts with IRF3/IRF7 and Pellino1 to drive antiviral IFNβ production (PMID:23846693). In muscle, DEAF1 is a FOXO-regulated factor that represses the autophagy genes Pik3c3 and Atg16l1 and drives mTOR transcription, becoming elevated in aged and cachectic muscle stem cells (PMID:38963021, PMID:41284871). De novo SAND-domain and NLS missense/deletion variants cause an intellectual disability disorder by impairing DNA binding and transcriptional regulation and acting as dominant negatives, with conditional brain knockout mice showing memory deficits, anxiety, and reduced dendritic spine density (PMID:24726472, PMID:28940898, PMID:35981081).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1996 High

    Established DEAF1 as a sequence-specific DNA-binding cofactor by showing it binds a defined site in the Deformed homeotic response element and is required for Deformed-dependent activation.

    Evidence Affinity isolation from Drosophila nuclear extracts with response-element mutagenesis and embryonic reporter assays

    PMID:8617243

    Open questions at the time
    • Mammalian role not addressed
    • Domain responsible for binding not yet mapped
  2. 1998 High

    Defined the mammalian DEAF1/NUDR consensus motif and showed nuclear localization is required for transcriptional activity, framing it as a regulated nuclear transcription factor.

    Evidence SELEX, EMSA, DNase I footprinting, NLS mutagenesis and reporter assays

    PMID:9773984

    Open questions at the time
    • Endogenous target genes not yet identified
    • Mechanism of activation vs repression unresolved
  3. 1999 High

    Localized the DNA-binding domain by deletion mapping and demonstrated DEAF1 represses the hnRNP A2/B1 promoter and its own 5'-UTR, introducing autoregulation.

    Evidence Deletion constructs, photocrosslinking, footprinting and reporter assays

    PMID:10521432

    Open questions at the time
    • Corepressor machinery not identified
    • Structural basis of binding unknown
  4. 2002 High

    Showed DEAF1 is essential for early development and broadly chromatin-associated, expanding it from a single-gene cofactor to a global regulator.

    Evidence Drosophila loss/gain-of-function genetics and polytene chromosome immunostaining

    PMID:12112874

    Open questions at the time
    • Direct target genes in vivo undefined
    • Mammalian developmental role not tested here
  5. 2004 High

    Defined the in vivo mammalian developmental role and a shared pathway with LMO4 in neural tube closure and skeletal patterning.

    Evidence Deaf-1 and Lmo4 knockout mice with embryo and skeletal phenotyping

    PMID:14966286

    Open questions at the time
    • Molecular nature of Deaf1-LMO4 interaction not yet structural
    • Target genes mediating phenotypes unknown
  6. 2004 High

    Resolved domain architecture controlling localization and DNA binding, showing a CRM1-dependent NES, a self-interaction region, and that protein interaction at the SAND/zinc motif is required for DNA recognition.

    Evidence Fusion protein localization, leptomycin B, leucine/cysteine mutagenesis, GST pulldowns and in vivo interaction assays

    PMID:15161925

    Open questions at the time
    • Physiological partners at the interaction domain not all identified
    • Regulation of shuttling not linked to signaling
  7. 2006 High

    Demonstrated that DEAF1 transcriptional activity is intrinsic and cell-type-dependent (repressor vs enhancer) at the 5-HT1A promoter and requires histone deacetylation.

    Evidence Multi-cell-line luciferase assays, Gal4DBD fusion at heterologous element, trichostatin A treatment

    PMID:16467535

    Open questions at the time
    • Identity of cell-type-specific cofactors switching activity unknown
    • In vivo serotonergic consequence not yet shown
  8. 2009 High

    Identified DEAF1 control of peripheral tissue antigen expression in lymph node stroma and a dominant-negative splice isoform elevated in autoimmune diabetes, linking it to immune tolerance.

    Evidence Reporter assays, siRNA, expression profiling and RT-PCR in mouse and human tissue

    PMID:19668219

    Open questions at the time
    • Splicing regulation of Var1 not yet defined
    • Direct PTA promoter targets not all mapped
  9. 2009 High

    Placed Drosophila Deaf1 downstream of NF-κB factors in Toll-dependent antifungal immunity, establishing an innate immune function.

    Evidence Genome-wide RNAi screen, in vivo knockdown, infection survival and epistasis

    PMID:20375635

    Open questions at the time
    • Mammalian innate immune role not addressed here
    • Mechanism of antimicrobial gene induction unknown
  10. 2012 Medium

    Mapped the LMO4-binding region as an intrinsically disordered segment flanked by a tetramer-forming coiled-coil, and showed LMO4 modulates DEAF1 nuclear export.

    Evidence GST pulldowns, cell-based export assay and coiled-coil characterization

    PMID:22723967

    Open questions at the time
    • Structural detail of complex not yet resolved
    • Single lab
  11. 2012 Medium

    Connected DEAF1 to the DNA-PK machinery, showing Ku70/Ku80 binding and DNA-PK phosphorylation of DEAF1 with DNA competing for the interaction.

    Evidence GST pulldown/MS, reciprocal Co-IP, in vitro kinase assay and EMSA

    PMID:22442688

    Open questions at the time
    • Functional consequence of phosphorylation unresolved
    • Single lab without in vivo validation
  12. 2012 Medium

    Defined a downstream translational output of DEAF1 by showing it transcriptionally controls Eif4g3/eIF4GII and thereby polysomal translation in lymph node stroma.

    Evidence Knockout/siRNA, RT-PCR, polysome profiling and western blot

    PMID:22923498

    Open questions at the time
    • Generality beyond stromal cells unknown
    • Single lab
  13. 2012 High

    Linked DEAF1 to serotonergic neurotransmission in vivo, showing region-specific repression of the 5-HT1A autoreceptor and enhancement of the heteroreceptor.

    Evidence Knockout mice with qPCR, ISH, immunofluorescence, ChIP and EMSA

    PMID:22232550

    Open questions at the time
    • Behavioral/affective consequences not directly tested
    • Switch mechanism between brain regions unresolved
  14. 2013 High

    Provided the MYND domain structure and showed it recruits NCoR/SMRT corepressors, defining the structural basis of DEAF1 repression.

    Evidence Solution NMR structure, titration mapping and peptide binding

    PMID:23372760

    Open questions at the time
    • Corepressor recruitment not validated on endogenous targets
    • Activator mechanism still unexplained
  15. 2013 High

    Established a positive innate immune role in mammals, with DEAF1 binding the IFNβ promoter and partnering IRF3/IRF7 and Pellino1 to drive IFNβ production.

    Evidence Reciprocal Co-IP, ChIP, siRNA and IFNβ ELISA in virus/poly(I:C)-challenged MEFs

    PMID:23846693

    Open questions at the time
    • Role of Pellino1 phosphorylation in vivo not resolved
    • How DEAF1 cooperates with IRFs structurally unknown
  16. 2014 High

    Solved the LMO4 LIM2–DEAF1 complex, showing disorder-to-order folding on binding and that DEAF1 competes with LDB1 and CtIP for LMO4, defining LMO4 as a shared interaction hub.

    Evidence NMR structure of tethered complex, yeast two-hybrid and mutagenic scanning

    PMID:25310299

    Open questions at the time
    • Functional outcome of LMO4 competition on target genes unknown
  17. 2014 High

    Refined the DNA recognition code to variably spaced unmethylated dual CpG motifs, establishing methylation sensitivity and an endogenous EIF4G3 target.

    Evidence Anchored-CpG SELEX, EMSA and ChIP at the EIF4G3 promoter

    PMID:25531106

    Open questions at the time
    • Genome-wide occupancy not mapped
    • Link of methylation sensitivity to physiology untested
  18. 2014 High

    Established DEAF1 as an intellectual disability gene, with SAND-domain de novo missense variants impairing transcriptional activity and brain-specific knockout causing cognitive deficits.

    Evidence Exome sequencing, reporter assays and conditional brain knockout behavioral phenotyping

    PMID:24726472

    Open questions at the time
    • Precise neuronal targets driving cognition unknown
    • Dominant vs recessive mechanism not yet resolved
  19. 2014 Medium

    Defined how the dominant-negative Deaf1-Var1 isoform is generated, identifying inflammation- and hyperglycemia-driven splicing via Srsf10 and Ptbp2.

    Evidence NOD mouse models, isoform RT-PCR and splicing factor overexpression with reporters

    PMID:25187368

    Open questions at the time
    • Direct splicing factor binding sites not mapped
    • Single lab
  20. 2017 Medium

    Extended the disease mechanism by showing SAND-domain variants reduce DNA-binding affinity and an NLS deletion variant sequesters DEAF1 in the cytoplasm and binds wild-type protein, supporting dominant-negative action.

    Evidence Reporter assays, EMSA and immunofluorescence localization

    PMID:28940898

    Open questions at the time
    • Dominant-negative effect not yet shown at endogenous targets
    • Single lab
  21. 2023 Medium

    Confirmed the dominant-negative mechanism transcriptome-wide, showing de novo DNA-binding-domain variants phenocopy DEAF1 deletion and fail to rescue, and linked Deaf1 loss to reduced dendritic spine density.

    Evidence Conditional KO hippocampal RNA-seq, CRISPR deletion, rescue assays and spine imaging

    PMID:35981081

    Open questions at the time
    • Causal target genes for spine phenotype not pinpointed
    • Single lab
  22. 2023 Medium

    Added phospho-regulation of DEAF1 by GSK3β at the 5-HT1A promoter, with GSK3 inhibitors reversing repression and the Y300F mutant augmenting repressor function.

    Evidence Reporter assays with GSK3 inhibitors and phosphosite mutagenesis

    PMID:37958600

    Open questions at the time
    • Direct in vitro phosphorylation not demonstrated
    • In vivo relevance to behavior untested
  23. 2024 High

    Defined DEAF1 as a FOXO-regulated autophagy repressor that directly represses Pik3c3 and Atg16l1, controlling muscle stem cell survival and elevated in aging and cachexia.

    Evidence ChIP, loss/gain-of-function in MuSCs, autophagy flux assays and in vivo aging/cachexia models

    PMID:38963021

    Open questions at the time
    • FOXO–DEAF1 promoter regulation not structurally defined
    • Single lab
  24. 2025 Medium

    Positioned DEAF1 as an upstream driver of mTORC1 in aged muscle by increasing mTOR transcription, with exercise suppressing it via FOXO to restore proteostasis.

    Evidence Deaf1 gain/loss in muscle, mTOR reporter and mTORC1 activity assays, FOXO inhibition and exercise intervention

    PMID:41284871

    Open questions at the time
    • Direct DEAF1 occupancy of the mTOR promoter not shown
    • Single lab
  25. 2025 Medium

    Revealed a cancer-relevant dual function in which SAND-mediated RAD50 activation engages ATM repair while MYND-mediated AP-2α recruitment suppresses GSDME pyroptosis in multiple myeloma.

    Evidence ChIP, Co-IP, high-throughput target sequencing and functional assays in vitro and in vivo

    PMID:41421151

    Open questions at the time
    • Generality beyond multiple myeloma unknown
    • Single lab with novel claims
  26. 2025 Medium

    Connected DEAF1 to a chromatin remodeling coactivator, showing SAYP (Brahma complex) interaction and pathogen-specific co-recruitment to antimicrobial peptide loci.

    Evidence Co-IP with domain mapping, ChIP and RNAi in Drosophila S2 cells

    PMID:41862015

    Open questions at the time
    • Mammalian conservation of SAYP interaction untested
    • Single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single sequence-specific factor switches between repressor and activator outputs across cell types and biological processes remains the central open question.
  • No genome-wide occupancy map integrating contexts
  • Cofactor switch governing activation vs repression undefined
  • Integration of phosphorylation, splicing, and shuttling into a unified regulatory model lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-112316 Neuronal System 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
IRF3IRF7LMO4NCOR1PELI1TFAP2AXRCC5XRCC6

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 DEAF-1 (Deformed epidermal autoregulatory factor-1) is a sequence-specific DNA-binding protein isolated from Drosophila nuclear extracts that binds a specific site in the Deformed homeotic response element, functioning as a cofactor required for Deformed-dependent transcriptional activation. Mutations improving DEAF-1 binding increased embryonic expression; mutations diminishing binding reduced expression. Protein-DNA binding assay (affinity isolation from nuclear extracts), in vitro mutagenesis of response element, reporter gene assays in Drosophila embryos The EMBO journal High 8617243
1998 The mammalian DEAF-1 homolog NUDR is a nuclear transcriptional regulator that binds a consensus DNA motif (TTCGGGNNTTTCCGG/TTCG core) identified by SELEX from random oligonucleotide libraries; nuclear localization depends on an NLS whose mutation causes cytoplasmic mislocalization and eliminates transcriptional activation. NUDR activates the proenkephalin promoter up to 41-fold and is displaced from RARE sequences by RAR/RXR complexes. SELEX, mobility shift assays, DNase I footprinting, site-directed mutagenesis of NLS, GFP fusion protein localization, transient transfection reporter assays, immunocytochemistry Molecular endocrinology High 9773984
1999 NUDR/DEAF-1 DNA binding domain was localized to amino acids 167–368 by deletion analysis; the domain contains a proline-rich region and a Myc-type HLH-like motif but not the C-terminal zinc finger. NUDR represses the hnRNP A2/B1 promoter ~65–70% through binding motifs (TTC(C/G)G) in the 5′-UTR of the hnRNP A2/B1 gene, and this repression also operates on NUDR's own 5′-UTR, suggesting autoregulation. NUDR protein deletion constructs, site-specific DNA photocrosslinking, DNase I footprinting, transient transfection reporter assays The Journal of biological chemistry High 10521432
2002 Drosophila DEAF-1 is required for early embryonic development: maternal/zygotic DEAF-1 mutations cause embryonic arrest prior to zygotic segmentation gene expression. DEAF-1 protein associates with many discrete sites on polytene chromosomes, indicating it is a broad regulator of gene expression. Overexpression causes defects in dorsal epidermis migration/closure and disrupts eye and wing development. Genetic loss-of-function (maternal/zygotic mutants), gain-of-function overexpression, polytene chromosome immunostaining Genesis High 12112874
2004 Deaf-1 knockout mice display defects in neural tube closure (exencephaly), homeotic skeletal transformations (cervical vertebrae and rib cage), overlapping with but distinct from LMO4 knockout phenotypes, indicating that Deaf-1 and LMO4 function in a shared pathway controlling neural tube closure and anteroposterior skeletal patterning in vivo. Gene knockout in mice (Deaf-1 and Lmo4 null alleles), embryo and skeletal phenotypic analysis, genetic epistasis by overlapping phenotype comparison Molecular and cellular biology High 14966286
2004 DEAF-1 contains a CRM1-dependent nuclear export signal (NES) with novel leucine spacing (LXLX(6)LLX(5)LX(2)L) at amino acids 454–476 adjacent to the MYND domain; mutation of key leucines or leptomycin B treatment eliminates nuclear export. A DEAF-1/DEAF-1 self-interaction domain maps to this NES region. A second protein-protein interaction domain at aa 243–306 encompasses the SAND domain and an adjacent zinc-binding motif; mutation of conserved cysteines/histidine in the zinc motif eliminates both protein interaction and DNA binding, showing protein-protein interaction is required for DNA recognition. Fluorescent fusion protein localization, leptomycin B treatment, leucine mutagenesis, in vitro GST pull-downs, in vivo fluorescent protein interaction assay, deletion mapping The Journal of biological chemistry High 15161925
2006 Deaf-1/NUDR exhibits cell-type-specific transcriptional activity at the 5-HT1A promoter C(-1019) allele: it represses transcription in serotonergic raphe RN46A cells but enhances transcription in nonserotonergic cells (SN48, SKN-SH, NG108-15). A Gal4DBD-Deaf-1 fusion protein recapitulates these opposite activities at a heterologous Gal4 element, demonstrating the activity is intrinsic to Deaf-1. Both repressor and enhancer activities require histone deacetylation (blocked by trichostatin A). Luciferase reporter assays in multiple cell lines, Gal4DBD-Deaf-1 fusion protein assays at heterologous element, trichostatin A (HDAC inhibitor) treatment The Journal of neuroscience High 16467535
2009 The transcriptional regulator Deaf1 controls expression of peripheral tissue antigen (PTA) genes in pancreatic lymph node stromal cells. An alternatively spliced dominant-negative Deaf1 isoform (Deaf1-Var1) suppresses PTA expression by inhibiting canonical Deaf1 transcriptional activity, and this isoform is elevated during insulitis in NOD mice and in type 1 diabetes patients. Reporter gene assays (luciferase), siRNA knockdown, gene expression profiling, RT-PCR in mouse and human lymph node samples Nature immunology High 19668219
2009 Drosophila Deaf1 is required for Toll-pathway-dependent innate immune responses: RNAi knockdown of Deaf1 reduces expression of the antifungal peptide gene Drosomycin and impairs survival after fungal (but not E. coli) infection. Epistasis analysis places Deaf1 downstream of the NF-κB factors Dorsal and Dif. Genome-wide RNAi screen, in vivo RNAi knockdown, survival assays after infection, genetic epistasis analysis Journal of innate immunity High 20375635
2012 Deaf-1 in vivo represses 5-HT1A autoreceptor expression in dorsal raphe (serotonergic) neurons while enhancing postsynaptic 5-HT1A heteroreceptor expression in frontal cortex. Deaf-1 knockout mice have increased 5-HT1A mRNA, protein, and positive cell counts in dorsal raphe but decreased 5-HT1A in frontal cortex, and reduced serotonin levels in raphe. A functional Deaf-1 binding site on the mouse 5-HT1A promoter was confirmed by ChIP and in vitro binding. Deaf-1 knockout mice, quantitative RT-PCR, in situ hybridization, immunofluorescence, ChIP, EMSA The Journal of biological chemistry High 22232550
2012 DEAF1 interacts with the Ku70 (XRCC6) and Ku80 (XRCC5) subunits of the DNA-PK complex. The interaction is mediated through DEAF1's DNA binding domain and the C-terminal Bax-binding region of Ku70. DEAF1 is phosphorylated by DNA-PK in vitro in a DNA-independent manner. DEAF1 binding sites in DNA inhibit the DEAF1–Ku70 interaction, suggesting competitive regulation. GST pulldown with mass spectrometry identification, co-immunoprecipitation of epitope-tagged proteins in cells, in vitro kinase assay, EMSA PloS one Medium 22442688
2012 DEAF1 regulates translation in lymph node stromal cells by controlling transcription of Eif4g3 (encoding eIF4GII). Deaf1 KO and Deaf1 silencing reduce Eif4g3 expression and increase Caspase-3-mediated eIF4GII degradation; reduced eIF4GII leads to diminished polysomal translation of multiple genes including Anpep. Deaf-1 knockout mice, siRNA silencing, RT-PCR, polysome profiling, western blotting Journal of molecular cell biology Medium 22923498
2013 The solution NMR structure of the human DEAF-1 MYND domain (residues 501–544) reveals a ββα fold with tandem zinc-binding sites in a cross-brace topology. The MYND domain binds peptides derived from SMRT and NCoR corepressors; the binding surface mapped by NMR titrations is similar to that of AML1/ETO MYND domain, demonstrating DEAF-1 recruits corepressors through this domain. NMR spectroscopy (solution structure determination), NMR titration mapping of binding surface, peptide binding assays PloS one High 23372760
2013 DEAF1 is a Pellino1-interacting protein required for IFNβ production. DEAF1 binds the IFNβ promoter and interacts with IRF3 and IRF7. DEAF1 is required for IFNβ transcription and secretion in MEFs infected with Sendai virus or transfected with poly(I:C), and for TLR3-dependent IFNβ production. The Pellino1–DEAF1 interaction is independent of Pellino1 E3 ligase activity but is weakened by Pellino1 phosphorylation. Co-immunoprecipitation (Pellino1–DEAF1 interaction), ChIP (DEAF1 on IFNβ promoter), co-IP of DEAF1 with IRF3/IRF7, siRNA knockdown of DEAF1, ELISA for IFNβ secretion The Journal of biological chemistry High 23846693
2012 A specific LMO4-binding domain in DEAF1 contains an intrinsically disordered region that directly contacts LMO4, flanked by a coiled-coil region containing the NES. The coiled-coil region can form tetramers. LMO4 modulates DEAF1 NES activity, causing nuclear accumulation of a construct containing the LMO4-interaction region of DEAF1. GST pulldowns, cell-based nuclear export assay, coiled-coil characterization PloS one Medium 22723967
2014 The NMR solution structure of the LMO4 LIM2–DEAF1 complex shows that the intrinsically disordered LMO4-binding domain of DEAF1 becomes structured upon binding LMO4 LIM2. Yeast two-hybrid and mutagenic analysis show DEAF1 binds both LIM domains of LMO4 at the same face used by LDB1 and CtIP/RBBP8, revealing LMO4 as a competitive hub in protein interaction networks. NMR spectroscopy (solution structure of tethered complex), yeast two-hybrid, mutagenic scanning PloS one High 25310299
2014 DEAF1 preferentially binds variably spaced (6–11 nt apart), unmethylated dual CpG dinucleotide motifs (repeated TTCGGG half-sites). Cytosine methylation of a single CpG half-site or alteration of the surrounding consensus eliminates DEAF1 binding. ChIP assay confirmed endogenous DEAF1 binds the EIF4G3 promoter at a sequence matching this consensus. SELEX with anchored CpG motif, EMSA, ChIP assay for endogenous DEAF1 at EIF4G3 promoter PloS one High 25531106
2014 All four identified de novo DEAF1 missense mutations in intellectual disability patients affect the SAND domain and impair DEAF1-dependent transcriptional regulation of the DEAF1 promoter in reporter assays. Conditional brain-specific Deaf1 knockout mice display memory deficits and increased anxiety-like behavior, establishing that SAND domain-mediated transcriptional activity is required for normal cognitive function. Luciferase reporter assays (DEAF1 promoter), conditional Deaf1 brain knockout mice (behavioral phenotyping), clinical exome sequencing American journal of human genetics High 24726472
2014 Inflammation and hyperglycemia independently drive alternative splicing of Deaf1 to the dominant-negative Deaf1-Var1 isoform in pancreatic lymph node stromal cells via distinct splicing factors: inflammation activates Srsf10 and hyperglycemia activates Ptbp2. Overexpression of PTBP2 and/or SRSF10 increases human DEAF1-VAR1 and reduces PTA expression. In vivo NOD mouse models (splenocyte injection, S961 insulin receptor agonist), RT-PCR for isoforms, overexpression of splicing factors in HEK293T cells, reporter assays Diabetes Medium 25187368
2017 De novo DEAF1 missense variants in the SAND domain (e.g., p.Gly212Ser) reduce DEAF1 transcriptional repression at the DEAF1 promoter and reduce affinity to consensus DEAF1 DNA binding sequences. A NLS domain deletion variant (p.Lys305del) localizes primarily to the cytoplasm and interacts with wild-type DEAF1, consistent with dominant-negative activity via cytoplasmic sequestration. Luciferase reporter assays, immunofluorescence localization, EMSA Human mutation Medium 28940898
2023 De novo heterozygous DEAF1 variants within the DNA binding domain act as dominant negatives: cells overexpressing de novo variants show gene expression profiles similar to CRISPR-Cas9-mediated DEAF1 deletion. Wild-type DEAF1 rescues altered gene expression in DEAF1-deleted cells whereas de novo variants do not. Loss of Deaf1 in mouse hippocampus reduces dendritic spine density. RNA-sequencing of conditional Deaf1 KO mouse hippocampus, CRISPR-Cas9 DEAF1 deletion, overexpression rescue assays, dendritic spine imaging Human molecular genetics Medium 35981081
2024 DEAF1 is a FOXO-regulated transcription factor that suppresses autophagy by binding the Pik3c3 and Atg16l1 promoters and repressing their expression. DEAF1 depletion induces autophagy and impairs muscle stem cell (MuSC) survival and differentiation; DEAF1 overexpression inactivates autophagy causing protein aggregation and cell death. DEAF1 is elevated in aged and cachectic MuSCs, and its manipulation attenuates muscle atrophy. ChIP (DEAF1 binding to Pik3c3 and Atg16l1 promoters), DEAF1 depletion and overexpression in MuSCs, autophagy flux assays, in vivo mouse models (aging, cancer cachexia) Autophagy High 38963021
2025 DEAF1 acts as a key upstream driver of mTORC1 in aged skeletal muscle by increasing mTOR transcription. Elevated DEAF1 leads to impaired proteostasis and muscle senescence; exercise suppresses DEAF1 via FOXO activation, restoring mTORC1 balance. FOXO inhibition or Deaf1 overexpression blocks exercise-mediated restoration of muscle health. Deaf1 overexpression and depletion in mouse muscle, mTOR transcription reporter assays, mTORC1 activity measurements, FOXO inhibition, exercise intervention in mice Proceedings of the National Academy of Sciences of the United States of America Medium 41284871
2025 DEAF1 directly binds the RAD50 promoter via its SAND domain, upregulating RAD50 and activating the ATM DNA damage repair pathway. DEAF1 also recruits AP-2α through its MYND domain, leading to downregulation of FER tyrosine kinase, which impairs FER-mediated phosphorylation of GSDME and suppresses GSDME cleavage by caspase-3, thereby attenuating pyroptosis in multiple myeloma. ChIP (DEAF1 binding to RAD50 promoter via SAND domain), co-immunoprecipitation (DEAF1–AP-2α via MYND domain), high-throughput sequencing of DEAF1 targets, in vivo and in vitro functional assays Drug resistance updates Medium 41421151
2023 GSK3β phosphorylates DEAF1 and modulates its repressor activity at the 5-HT1A promoter. Lithium and selective GSK3 inhibitors (CHIR-99021, AR-014418) attenuate and reverse Deaf1-mediated repression of 5-HT1A transcription at concentrations that maximally inhibit GSK3β. The Y300F point mutation in Deaf1 augments its repressor function, while other predicted phosphorylation site mutants had no effect. Luciferase reporter assays (5-HT1A promoter), GSK3β inhibitor treatments, site-directed mutagenesis of DEAF1 phosphorylation sites, TCF/LEF reporter for GSK3β activity International journal of molecular sciences Medium 37958600
2025 DEAF1 interacts with the transcriptional coactivator SAYP (a component of the Brahma chromatin remodeling complex) via immunoprecipitation; specific domains mediating their association were mapped. SAYP and DEAF1 are co-recruited to antimicrobial peptide (AMP) gene regions in a gene- and pathogen-specific manner in Drosophila S2 cells after immune challenge. Immunoprecipitation (SAYP–DEAF1 interaction), domain mapping, ChIP for recruitment to AMP gene loci, RNAi knockdown of SAYP and DEAF1 Biochimica et biophysica acta. Gene regulatory mechanisms Medium 41862015

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 DEAF-1, a novel protein that binds an essential region in a Deformed response element. The EMBO journal 126 8617243
2009 Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes. Nature immunology 116 19668219
2006 Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism. The Journal of neuroscience : the official journal of the Society for Neuroscience 110 16467535
2004 Defective neural tube closure and anteroposterior patterning in mice lacking the LIM protein LMO4 or its interacting partner Deaf-1. Molecular and cellular biology 105 14966286
2008 Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder. The international journal of neuropsychopharmacology 78 18561871
1998 Characterization of a nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR) transcriptional regulator protein. Molecular endocrinology (Baltimore, Md.) 76 9773984
2012 Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice. The Journal of biological chemistry 70 22232550
2014 Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. American journal of human genetics 59 24726472
1999 Nuclear DEAF-1-related (NUDR) protein contains a novel DNA binding domain and represses transcription of the heterogeneous nuclear ribonucleoprotein A2/B1 promoter. The Journal of biological chemistry 51 10521432
2002 DEAF-1 function is essential for the early embryonic development of Drosophila. Genesis (New York, N.Y. : 2000) 46 12112874
2009 A large-scale RNAi screen identifies Deaf1 as a regulator of innate immune responses in Drosophila. Journal of innate immunity 39 20375635
2009 Chronic social defeat downregulates the 5-HT1A receptor but not Freud-1 or NUDR in the rat prefrontal cortex. Neuroscience letters 37 20026183
2012 Reduced DEAF1 function during type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. Journal of molecular cell biology 35 22923498
2008 Deaf-1 regulates epithelial cell proliferation and side-branching in the mammary gland. BMC developmental biology 30 18826651
2019 De novo and biallelic DEAF1 variants cause a phenotypic spectrum. Genetics in medicine : official journal of the American College of Medical Genetics 29 30923367
2013 DEAF1 is a Pellino1-interacting protein required for interferon production by Sendai virus and double-stranded RNA. The Journal of biological chemistry 28 23846693
2004 Identification of a nuclear export signal and protein interaction domains in deformed epidermal autoregulatory factor-1 (DEAF-1). The Journal of biological chemistry 28 15161925
2015 Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy. Journal of medical genetics 26 26048982
2014 Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1. The international journal of neuropsychopharmacology 25 24946016
2016 Sex-dependent adaptive changes in serotonin-1A autoreceptor function and anxiety in Deaf1-deficient mice. Molecular brain 24 27488351
2017 Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype. Human mutation 23 28940898
2013 Structural and functional analysis of the DEAF-1 and BS69 MYND domains. PloS one 22 23372760
2012 Contribution of DEAF1 structural domains to the interaction with the breast cancer oncogene LMO4. PloS one 21 22723967
2014 Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly. American journal of medical genetics. Part A 20 24668509
2014 Inflammation and hyperglycemia mediate Deaf1 splicing in the pancreatic lymph nodes via distinct pathways during type 1 diabetes. Diabetes 19 25187368
2024 FOXO-regulated DEAF1 controls muscle regeneration through autophagy. Autophagy 18 38963021
2012 Deformed epidermal autoregulatory factor-1 (DEAF1) interacts with the Ku70 subunit of the DNA-dependent protein kinase complex. PloS one 13 22442688
2016 Identification of a syndrome comprising microcephaly and intellectual disability but not white matter disease associated with a homozygous c.676C>T p.R226W DEAF1 mutation. American journal of medical genetics. Part A 12 26834045
2014 DEAF1 binds unmethylated and variably spaced CpG dinucleotide motifs. PloS one 12 25531106
2012 17β-estradiol-induced regulation of the novel 5-HT1A-related transcription factors NUDR and Freud-1 in SH SY5Y cells. Cellular and molecular neurobiology 12 22328058
2014 The structure of an LIM-only protein 4 (LMO4) and Deformed epidermal autoregulatory factor-1 (DEAF1) complex reveals a common mode of binding to LMO4. PloS one 10 25310299
2019 Impaired memory and marble burying activity in deformed epidermal autoregulatory factor 1 (Deaf1) conditional knockout mice. Behavioural brain research 8 31783086
2023 Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders. Human molecular genetics 7 35981081
2022 Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis. Discover oncology 7 36520265
2023 Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review. Frontiers in neurology 4 38073621
2021 De novo variants of DEAF1 cause intellectual disability in six Chinese patients. Clinica chimica acta; international journal of clinical chemistry 4 33705764
2013 Backbone and side-chain assignments of a tethered complex between LMO4 and DEAF-1. Biomolecular NMR assignments 4 23417771
2025 Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging. Proceedings of the National Academy of Sciences of the United States of America 3 41284871
2023 Transcriptional Regulation of the Human 5-HT1A Receptor Gene by Lithium: Role of Deaf1 and GSK3β. International journal of molecular sciences 2 37958600
2025 Integrated functional genomics-identified DEAF1 in oxidative stress and hepatocellular carcinoma development. Carcinogenesis 1 40554679
2025 DEAF1 - a transcriptional brake on muscle autophagy. Autophagy 1 41456123
2026 The First Reported Case of an Inherited Pathogenic Variant in DEAF1 From a Parent With Milder Phenotype Provides Evidence of Variable Gene Expressivity of the DEAF1-Associated Vulto-van Silfout-de Vries Syndrome (VSVS). American journal of medical genetics. Part A 0 41518091
2026 Transcription coactivator SAYP cooperates with transcription factor DEAF1 to mediate immune defense in Drosophila melanogaster. Biochimica et biophysica acta. Gene regulatory mechanisms 0 41862015
2025 Sleep disturbances associated with DEAF1 pathogenic variants. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 0 39172073
2025 DEAF1 confers resistance to adriamycin-induced apoptosis and pyroptosis in multiple myeloma. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 0 41421151

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