Affinage

HSF4

Heat shock factor protein 4 · UniProt Q9ULV5

Length
492 aa
Mass
53.0 kDa
Annotated
2026-06-10
78 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSF4 is a heat shock transcription factor that serves as the master regulator of lens fiber cell differentiation and terminal denucleation, and it functions distinctly from other HSF family members because it lacks the C-terminal HR-C autoinhibitory domain and therefore forms constitutively active DNA-binding trimers in the absence of stress (PMID:8972228). Alternative splicing generates two isoforms of opposite activity: HSF4a acts as a repressor while HSF4b is a transcriptional activator, both forming trimers but only HSF4b activating target genes (PMID:10488131). In the lens, HSF4 is the predominant postnatal HSF and binds HSE elements in the promoters of lens structural and differentiation genes, directly activating gamma-crystallin and beaded filament proteins Bfsp1/Bfsp2 (PMID:15308659, PMID:19224648) while repressing vimentin and FGF genes to control proliferation versus differentiation (PMID:15483628, PMID:19628735). HSF4 drives organelle clearance and denucleation by directly activating the nuclease DLAD/DNase2β (PMID:23507146) and the autophagy gene ATG9a (PMID:37266953), and by stabilizing nuclear p53 to engage Fas/Bax and p21-dependent G1/S arrest and apoptotic differentiation signals (PMID:28981088, PMID:25940838); it additionally supports genome integrity by activating Rad51 (PMID:22587838). Loss-of-function and DNA-binding-domain missense mutations in HSF4 cause congenital and age-related cataract by abolishing HSE recognition, oligomerization, or transactivation (PMID:20670914, PMID:32647819), and HSF4 also regulates retinal visual-cycle genes RPE65 and RDH5 with mutant mice showing retinal degeneration (PMID:40023307). HSF4 cross-regulates the heat shock response by binding HSP and αB-crystallin promoters and by directly interacting with HSF1 to drive its cytosolic retention and lysosomal/proteasomal degradation (PMID:25601714), and HSF4 protein itself is destabilized through BCAS2-mediated ubiquitination at Lys206 (PMID:26319152). Beyond the lens, HSF4 represses HIF-1α transcription together with HSF2 (PMID:21258402) and, in cancer, acts as a context-dependent activator of c-MET, MBOAT1/2, and inflammatory programs (PMID:36229759, PMID:41622376).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Established that HSF4 is mechanistically distinct from other HSFs by forming constitutive DNA-binding trimers and repressing rather than activating classic heat shock genes, reframing HSF4 as a negative regulator.

    Evidence EMSA, reporter assays, and Northern blot of endogenous HSPs after HSF4 overexpression in HeLa cells

    PMID:8972228

    Open questions at the time
    • Did not resolve why HR-C loss confers constitutive trimerization at atomic level
    • Physiological tissue context not addressed
  2. 1999 High

    Resolved how a single repressor protein could also activate genes by showing alternative splicing produces HSF4a (repressor) and HSF4b (activator).

    Evidence RT-PCR, exon mapping, yeast complementation, and reporter assays under stress

    PMID:10488131

    Open questions at the time
    • Tissue-specific splicing control not defined
    • Structural basis for opposite activities of trimer-forming isoforms unresolved
  3. 2004 High

    Defined HSF4's physiological role as required for lens fiber differentiation and identified FGF gene regulation and competition with HSF1 as a proliferation-controlling mechanism.

    Evidence HSF4 knockout mice with histology, IHC, Q-PCR, and proliferation assays; EMSA on αB-crystallin promoter in postnatal lens

    PMID:15308659 PMID:15483628

    Open questions at the time
    • Direct FGF promoter binding not fully resolved
    • How HSF4 switches between activation and repression in lens not defined
  4. 2008 High

    Showed HSF4 acts at the chromatin level genome-wide, modifying H3K9 methylation and facilitating HSF1 binding, linking it to non-classic heat shock gene induction.

    Evidence ChIP genomic binding analysis with histone modification assays in HSF4-null lens

    PMID:18755693

    Open questions at the time
    • Enzymatic partner responsible for H3K9 demethylation not identified
    • Mechanism of facilitating HSF1 binding incompletely defined
  5. 2009 High

    Identified direct lens target genes governing denucleation and structure, establishing HSF4 as both activator (crystallins, beaded filaments) and repressor (vimentin) in fiber cell maturation.

    Evidence EMSA, luciferase, ChIP, proteomics in Hsf4 knockout mice

    PMID:19224648 PMID:19628735

    Open questions at the time
    • Determinants of activation versus repression at individual promoters unresolved
    • Post-translational modification of αA-crystallin link mechanism unclear
  6. 2011 Medium

    Extended HSF4 function beyond lens by showing it cooperates with HSF2 to repress HIF-1α transcription in cancer cells through balanced HSE occupancy.

    Evidence EST screen, ChIP, siRNA, reporter assays, and VEGF measurement in breast cancer cells

    PMID:21258402

    Open questions at the time
    • Single-lab target identification
    • Physiological relevance outside cultured cancer cells not established
  7. 2012 Medium

    Placed HSF4 upstream of apoptosis/p53-driven differentiation and DNA repair by demonstrating it stabilizes nuclear p53, activates Rad51, and that its deletion suppresses tumors with senescence.

    Evidence TALEN zebrafish knockout with mRNA rescue, ChIP/reporter on Rad51, comet assay, and Hsf4/p53/Arf genetic crosses with senescence readouts

    PMID:22355043 PMID:22587838 PMID:28981088

    Open questions at the time
    • Mechanism of p53 stabilization molecularly undefined at this stage
    • Direct versus indirect contributions to senescence not separated
  8. 2013 High

    Defined the denucleation effector mechanism by showing HSF4 directly activates the DLAD/DNase2β nuclease, and that cataract mutations abolish this binding.

    Evidence ChIP, luciferase, DNase activity assays, and morpholino knockdown in zebrafish

    PMID:23507146

    Open questions at the time
    • Whether DLAD activation alone suffices for denucleation not isolated
  9. 2013 Medium

    Dissected HSF4 domain architecture and cell-type-dependent promoter occupancy, showing transactivation requires C-terminal activation domains and that occupancy is lineage-restricted.

    Evidence FLAG-tagged mutant expression, EMSA, reporter, stability assays, and comparative ChIP in epithelial cells versus fibroblasts

    PMID:23264262 PMID:24045990

    Open questions at the time
    • Factors controlling cell-type-specific occupancy unidentified
    • Some mutants bind DNA yet lose activation by unresolved mechanism
  10. 2015 High

    Established reciprocal regulation between HSF4 and the heat shock machinery: HSF4b binds HSF1 to drive its degradation, stabilizes p53 to arrest the cell cycle, and is itself ubiquitinated by BCAS2 at K206.

    Evidence Co-IP, ChIP, inhibitor studies, ubiquitination assays, K206R mutagenesis, and reconstitution in Hsf4-/- cells

    PMID:25601714 PMID:25940838 PMID:26319152

    Open questions at the time
    • E3 ligase responsible for HSF1 degradation not identified
    • BCAS2-associated ligase complex composition undefined
  11. 2019 High

    Provided the structural basis for cataract pathogenesis by solving the HSF4 DNA-binding domain crystal structure and classifying mutation mechanisms.

    Evidence X-ray crystallography of WT and K23N DBD with molecular dynamics and in silico mutagenesis

    PMID:32647819

    Open questions at the time
    • Full-length trimer and activation-domain structure not solved
    • DNA-bound complex structure not determined experimentally
  12. 2022 Medium

    Demonstrated oncogenic and signaling roles in cancer, showing HSF4 activates c-MET to drive ERK/AKT signaling and is gated by FGD3-controlled nuclear translocation feeding NF-κB.

    Evidence ChIP, Western blot, siRNA rescue, and xenografts in colorectal and pancreatic cancer; Co-IP of FGD3-HSF4

    PMID:34975151 PMID:36229759

    Open questions at the time
    • Reconciliation with HSF4's tumor-suppressive role in p53/Arf context unresolved
    • Single-lab cancer findings
  13. 2023 Medium

    Broadened HSF4's terminal-differentiation program to autophagy and stress-response contexts by identifying ATG9a as a direct lens target and a UV-induced HSF4/COIL complex redirecting target binding via R-loop recognition.

    Evidence ChIP/reporter on ATG9a with HSF4del42 mice and rapamycin rescue; Co-IP, R-loop detection, and ChIP for HSF4-COIL in UV-irradiated skin

    PMID:37266953 PMID:37461263

    Open questions at the time
    • Mechanism of COIL-driven target switching incompletely defined
    • Generality of skin inflammation role beyond UV not tested
  14. 2025 Medium

    Extended HSF4 transcriptional control to the retina and to ferroptosis defense, identifying RPE65/RDH5 visual-cycle genes and MBOAT1/2 lipid-metabolism genes as direct targets.

    Evidence ChIP/ChIP-seq, immunoblotting, ERG, AAV-HSF4b rescue in HSF4del42 mice; ferroptosis assays with MBOAT1/2 knockdown rescue and xenografts

    PMID:40023307 PMID:41622376

    Open questions at the time
    • Tissue specificity of ferroptosis regulation not established
    • Whether retinal and lens programs share regulatory logic unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HSF4 switches between activator and repressor states at different promoters and cell types, and the identity of the E3 ligase machinery degrading HSF1, remain unresolved.
  • No defined molecular determinant of activation-versus-repression switching
  • E3 ligase mediating HSF4-driven HSF1 degradation unidentified
  • No experimental full-length or DNA-bound structure

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 1
Partners
BCAS2COILFGD3HSF1HSF2P53

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 HSF4 forms a constitutively active DNA-binding trimer in the absence of stress, unlike other HSF family members. It lacks the carboxyl-terminal hydrophobic repeat (HR-C domain) present in all other vertebrate HSFs, which is involved in negative regulation of DNA binding. Overexpression of HSF4 in HeLa cells represses endogenous hsp70, hsp90, and hsp27 gene expression, demonstrating it acts as a transcriptional repressor rather than activator of heat shock genes. Transient transfection in HeLa cells, gel mobility shift assay (trimer formation), reporter assays, Northern blot for endogenous HSP expression Molecular and cellular biology High 8972228
1999 Alternative splicing of the HSF4 gene generates two isoforms with opposite transcriptional activities: HSF4a acts as an inhibitor/repressor of heat shock gene expression, while HSF4b acts as a transcriptional activator. Both isoforms form trimers constitutively, but only HSF4b complements the viability defect of yeast cells lacking HSF and activates target genes in response to heat shock and other stresses. RT-PCR, exon structure determination, transient transfection reporter assays, yeast complementation assay, stress induction experiments The Journal of biological chemistry High 10488131
2004 HSF4 is required for normal lens fiber cell differentiation and lens epithelial cell proliferation in mice. HSF4-null mice develop cataracts with decreased gamma-crystallin expression and inclusion-like structures in fiber cells. Loss of HSF4 leads to increased expression of FGF-1, FGF-4, and FGF-7, and increased lens epithelial cell proliferation and premature differentiation. HSF1 and HSF4 compete for regulation of FGF gene expression in the lens. HSF4 knockout mouse generation, histological analysis, immunohistochemistry, Western blot, Q-PCR, lens epithelial cell proliferation assays The EMBO journal High 15483628
2004 In the postnatal rat and human lens, HSF4 (not HSF1 or HSF2) is the predominant HSF expressed and binds specifically to the heat shock element (HSE) of the alphaB-crystallin gene promoter. HSF1 and HSF2 expression is largely fetal, while HSF4 expression is predominantly postnatal in the lens. Real-time PCR, immunoblotting, gel mobility shift assay (EMSA) with specific antibodies and HSE probes from alphaB-crystallin, Hsp70, and Hsp82 promoters The Journal of biological chemistry High 15308659
2008 HSF4 binds to various genomic regions in mouse lenses in vivo, including introns and distal regions of protein-coding genes, with substantial overlap with HSF1 and HSF2 binding regions. HSF4 binding induces demethylation of histone H3K9 on bound regions (chromatin modification). HSF4 is required for induction of a set of non-classic heat shock genes in response to heat shock, in part by facilitating HSF1 binding through chromatin modification. Chromatin immunoprecipitation (ChIP) with genomic region analysis, histone modification assays, heat shock gene expression analysis in HSF4-null lens The Journal of biological chemistry High 18755693
2009 HSF4 represses vimentin gene expression by binding to an HSE-like element in the vimentin promoter. Loss of HSF4 in knockout mice results in upregulated vimentin expression and impaired denucleation of lens fiber cells. 2D electrophoresis/mass spectrometry of lens proteins, Western blot, Q-PCR, immunofluorescence, EMSA, luciferase reporter assay, ChIP assay, Hsf4 knockout mouse model Investigative ophthalmology & visual science High 19628735
2009 Loss of HSF4 in knockout mice leads to cataracts through at least three mechanisms: (1) downregulation of gamma-crystallin (especially gamma S-crystallin); (2) decreased expression of lens beaded filament proteins Bfsp1 and Bfsp2; (3) loss of post-translational modifications of alphaA-crystallin. Dual-luciferase transcription activity assays confirmed gamma S-crystallin and Bfsp genes as direct HSF4 transcriptional targets. Hsf4 knockout mouse model, Q-PCR, dual-luciferase reporter assay, 2D electrophoresis of lens lysates BMC molecular biology High 19224648
2011 HSF4 (HSF2 and HSF4 together) binds to discontinuous heat shock element (HSE) sequences in the HIF-1α promoter to maintain steady-state repression of HIF-1α transcription and downstream VEGF production. Downregulation of either HSF2 or HSF4 activates HIF-1α transcription, and overexpression of either also activates it, indicating a critical balance is required. HSF2 and HSF4 displace each other from HSF/HSE complexes at the HIF-1α promoter. Genome-wide EST screen, ChIP assay, siRNA knockdown, reporter assays, VEGF measurement in breast cancer cells Oncogene Medium 21258402
2012 HSF4 promotes lens fiber cell differentiation by stabilizing p53 in the nucleus and activating p53 target genes Fas and Bax. In hsf4-null zebrafish, p53 and activated caspase-3 are decreased, terminal differentiation (organelle clearance/denucleation) is impaired. Microinjection of p53, fas, and bax mRNA into hsf4-null zebrafish embryos partially rescues the denucleation defect, placing HSF4 upstream of apoptosis-related differentiation signals. TALEN-mediated HSF4 knockout in zebrafish, immunofluorescence, Western blot, nuclear p53 localization in human lens epithelial cells, mRNA microinjection rescue experiment Cell death & disease High 28981088
2012 HSF4 contributes to DNA damage repair by binding to a heat shock element in the Rad51 promoter and upregulating Rad51 expression. Cataract-causing HSF4 mutations fail to bind the Rad51 promoter and fail to upregulate Rad51, resulting in unrepaired DNA strand breaks. HSF4 knockdown in zebrafish lens leads to increased DNA damage and decreased Rad51 protein. ChIP assay (HSF4 binding to Rad51 promoter), luciferase reporter assay, Western blot, DNA damage assays (comet assay), HSF4 knockdown in zebrafish Biochimica et biophysica acta Medium 22587838
2012 Deletion of hsf4 in mice suppresses spontaneous tumor development in p53- or Arf-deficient backgrounds, and hsf4-deficient mouse embryo fibroblasts exhibit cellular senescence with increased SA-β-galactosidase activity and elevated p21 and p27 cyclin-dependent kinase inhibitors. Genetic crosses of Hsf4-/- with p53-/- and Arf-/- mice, SA-β-galactosidase staining, Western blot for p21/p27, tumor incidence monitoring Molecular cancer research : MCR Medium 22355043
2013 HSF4 directly binds the DLAD (DNase 2β) promoter and promotes DLAD expression and DNase activity, thereby facilitating de-nucleation of lens fiber cells. Cataract-causing HSF4 mutations fail to bind the DLAD promoter, abrogating DLAD expression and DNase activity. HSF4 knockdown in zebrafish leads to incomplete lens de-nucleation and decreased DLAD expression/activity. ChIP assay (HSF4 binding to DLAD promoter), luciferase reporter assay, DNase activity assay, HSF4 morpholino knockdown in zebrafish Biochimica et biophysica acta High 23507146
2013 Three autosomal recessive HSF4 mutant proteins (G199EfsX15, R405X, M419GfsX29) are properly trafficked to the nucleus but exhibit abolished HSE-mediated luciferase reporter activation. G199EfsX15 and M419GfsX29 show decreased HSE DNA binding, while R405X shows increased HSE binding—yet all three lose transactivation function. The C-terminal region of HSF4 contains two activation domains and one repression domain that are critical for transcriptional activation. FLAG-tagged recombinant protein expression, Western blot, immunofluorescence (nuclear localization), EMSA (HSE DNA binding), luciferase reporter assay, protein stability assay Investigative ophthalmology & visual science High 24045990
2015 HSF4b promotes G1/S cell cycle arrest in human lens epithelial cells in a p53-dependent manner by recruiting p53 to the nucleus, stabilizing p53 protein (inhibiting ubiquitin-mediated degradation), and activating p53 targets p21. Cataract-causing HSF4 mutants fail to arrest the cell cycle and have no effect on proliferation. Cell cycle analysis (flow cytometry), BrdU proliferation assay, co-immunoprecipitation (HSF4-p53 interaction), Western blot, ubiquitination assay in human lens epithelial cells Biochimica et biophysica acta Medium 25940838
2015 HSF4b interacts directly with HSF1 via the N-terminal hydrophobic region of HSF4b binding the N-terminal hydrophobic region of HSF1. This interaction impairs HSF1's intramolecular interaction between N- and C-terminal hydrophobic regions, leading to HSF1 cytosolic retention and protein degradation via both lysosomal and proteasomal pathways. HSF4b directly binds promoters of Hsp90α, Hsp70.3, Hsp25, and αB-crystallin (but not Hsp70.1) and inhibits Hsf1 binding to the Hsp70.3 promoter. ChIP assay (promoter binding), co-immunoprecipitation (HSF4b-HSF1 interaction), Western blot, lysosome and proteasome inhibitor treatments, immunofluorescence (cytosolic retention of HSF1), reconstitution of Hsf4b in Hsf4-/- cells Biochimica et biophysica acta High 25601714
2015 BCAS2 interacts with HSF4 and negatively regulates HSF4 protein stability through ubiquitination. BCAS2 knockdown increases HSF4 protein half-life by reducing ubiquitination. Lysine 206 of HSF4 is identified as the key residue for ubiquitination; the HSF4-K206R mutant is resistant to BCAS2-mediated destabilization. Co-immunoprecipitation (BCAS2-HSF4 interaction), Western blot (protein stability/half-life assay), ubiquitination assay, site-directed mutagenesis (K206R), immunohistochemistry The international journal of biochemistry & cell biology Medium 26319152
2006 HSF4 acts as a repressor of the rat mrp3 (Abcc3) gene promoter: deletion of the HSF4 binding site in the mrp3 promoter significantly increases transcriptional activity under TNF-alpha stimulation, and endotoxin affects transcriptional activity specifically in C/EBPbeta and HSF4 double-deletion mrp3 promoter constructs. Promoter deletion analysis, luciferase reporter assay in hepatic cells, identification of HSF4 cis-element in mrp3 promoter Biochemical and biophysical research communications Low 17196161
2010 Five missense mutations in the DNA-binding domain of HSF4 associated with congenital cataract inhibit HSF4 DNA binding activity. HSF4 activates transcription of crystallin and beaded filament structural protein genes in lens epithelial cells. Two age-related cataract-associated mutations did not or only slightly alter HSF4 activity. EMSA (DNA binding), reporter assay (transcriptional activation), transient transfection of mutant HSF4 in lens epithelial cells Biochimica et biophysica acta Medium 20670914
2011 HSF4(lop11) mutant protein (loss of 132 C-terminal amino acids due to ETn insertion) fails to form trimers, abolishing HSE-mediated DNA binding and transactivation. Wild-type HSF4b nuclear trafficking is not affected by this truncation. Persistence of nuclei in postnatal lop11 lens fiber cells is the initial lens abnormality, confirming HSF4b's role in denucleation. EMSA (DNA binding and trimer formation), luciferase reporter assay, Western blot (protein stability), immunofluorescence (nuclear localization), histological analysis of lop11 mouse lenses Molecular vision Medium 22162625
2012 In epithelial cells, HSF4 occupies the αB-crystallin (CRYAB) promoter but not the HSP70 promoter, while HSF1 occupies only the HSP70 promoter in both epithelial cells and fibroblasts. In fibroblasts, HSF4 does not occupy either promoter. This cell-type-dependent promoter occupancy, rather than promoter architecture alone, controls differential heat shock gene expression. Chromatin immunoprecipitation (ChIP) in human retinal pigment epithelial cells and NIH3T3 fibroblasts, with specific antibodies against HSF1 and HSF4 Cell stress & chaperones Medium 23264262
2018 HSF4 directly binds the HSE element located at -389 bp to -362 bp upstream from the transcription start site of the HMOX-1 (heme oxygenase-1) promoter to activate HMOX-1 mRNA transcription and protein accumulation in human lens epithelial cells. siRNA knockdown of HSF4 inhibits HMOX-1 expression. ChIP assay (HSF4 binding to HMOX-1 promoter), luciferase reporter assay with HSE deletion, siRNA knockdown, RT-PCR, Western blot Gene Medium 29454088
2019 Crystal structures of the wild-type DNA-binding domain (DBD) of human HSF4 and the K23N mutant were determined. Structural analysis with DNA-binding modeling, in silico mutations, and molecular dynamics simulations identified four mechanisms by which missense mutations in HSF4-DBD cause cataract: disruption of HSE recognition, perturbation of protein-DNA interactions, alteration of protein folding, and inhibition of protein oligomerization. X-ray crystallography (high-resolution crystal structures of WT DBD and K23N mutant), molecular dynamics simulation, in silico mutagenesis, DNA-binding modeling Journal of structural biology: X High 32647819
2022 HSF4 directly binds the MET promoter (as confirmed by ChIP assay) to enhance c-MET expression, which activates downstream ERK1/2 and AKT signaling pathways in colorectal cancer cells. Restoration of c-MET expression abolishes the inhibitory effects of HSF4 knockdown on cell growth and invasion. ChIP assay (HSF4 binding to MET promoter), Western blot (c-MET, ERK1/2, AKT), siRNA knockdown, rescue experiments, xenograft mouse model Molecular and cellular biochemistry Medium 36229759
2022 FGD3 inhibits pancreatic cancer progression by binding HSF4 and preventing its nuclear translocation; FGD3 silencing activates NF-κB signaling by promoting HSF4 nuclear translocation and increasing p65 (RelA) expression. A FGD3/HSF4/p65 signaling axis was identified in pancreatic cancer cells. Co-immunoprecipitation (FGD3-HSF4 interaction), immunofluorescence (HSF4 nuclear localization), Western blot, siRNA knockdown, in vivo xenograft Oncogene Medium 34975151
2023 HSF4 directly transcriptionally activates ATG9a to facilitate autophagy and organelle degradation during lens terminal differentiation. HSF4del42 mutant mice show delayed organelle clearance and impaired autophagic flux. Rapamycin-mediated autophagy activation ameliorates organelle clearance defects in HSF4del42 lenses. The lens-specific ATG9a-X2 isoform (with short half-life) is identified as the predominant ATG9a form in lens. ChIP assay (HSF4 binding to ATG9a promoter), luciferase reporter assay, immunofluorescence and immunoblotting (organelle clearance/autophagy markers), HSF4del42 mutant mouse model, rapamycin treatment Investigative ophthalmology & visual science Medium 37266953
2023 Under UV irradiation, HSF4 forms a complex with COIL (coilin), and this HSF4/COIL complex changes its target gene binding preference due to COIL's ability to recognize R-loops that accumulate after UV-induced DNA damage. The HSF4-COIL complex enhances expression of inflammation- and aging-related genes including Atg7, Tfpi, and Lims1 in UV-irradiated skin. Transcriptome sequencing, co-immunoprecipitation (HSF4-COIL complex), R-loop detection, ChIP assay, drug screen for COIL-R-loop recognition inhibition Clinical and translational medicine Medium 37461263
2025 HSF4 directly binds to the promoters of RPE65 and RDH5 (visual cycle regulatory proteins) to regulate their expression in the retina. HSF4del42 mutant mice exhibit retinal degeneration with downregulation of RPE65, RDH5, and RLBP1, retinal gliosis, senescence markers, and impaired ERG responses. Intravitreal AAV-mediated delivery of HSF4b partially restores visual cycle protein expression and ERG responses. ChIP assay (HSF4 binding to RPE65 and RDH5 promoters), immunofluorescence, immunoblotting, ERG, AAV gene therapy rescue, HSF4del42 mutant mouse model Experimental eye research Medium 40023307
2026 HSF4 alleviates ferroptosis in colorectal cancer by transcriptionally activating MBOAT1 and MBOAT2 (lipid metabolism genes). HSF4 overexpression reduces lipid peroxidation and Fe2+ levels, and MBOAT1/2 knockdown reverses these effects. ChIP-seq identified MBOAT1/2 promoter regions as direct HSF4 binding targets. ChIP-seq (HSF4 binding to MBOAT1/2 promoters), ferroptosis assays (lipid peroxidation, Fe2+ levels, GPX4/SLC7A11/ACSL4 markers), siRNA knockdown rescue, in vivo xenograft Functional & integrative genomics Medium 41622376

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator. Molecular and cellular biology 276 8972228
2002 Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nature genetics 219 12089525
2004 HSF4 is required for normal cell growth and differentiation during mouse lens development. The EMBO journal 201 15483628
1999 The mammalian HSF4 gene generates both an activator and a repressor of heat shock genes by alternative splicing. The Journal of biological chemistry 132 10488131
2004 A homozygous splice mutation in the HSF4 gene is associated with an autosomal recessive congenital cataract. Investigative ophthalmology & visual science 95 15277496
2004 Developmentally dictated expression of heat shock factors: exclusive expression of HSF4 in the postnatal lens and its specific interaction with alphaB-crystallin heat shock promoter. The Journal of biological chemistry 70 15308659
2005 Locus heterogeneity in autosomal recessive congenital cataracts: linkage to 9q and germline HSF4 mutations. Human genetics 67 15959809
2009 Removal of Hsf4 leads to cataract development in mice through down-regulation of gamma S-crystallin and Bfsp expression. BMC molecular biology 66 19224648
2008 Analysis of HSF4 binding regions reveals its necessity for gene regulation during development and heat shock response in mouse lenses. The Journal of biological chemistry 62 18755693
2018 Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects. Human mutation 61 29314435
2025 Extracellular matrix stiffness regulates colorectal cancer progression via HSF4. Journal of experimental & clinical cancer research : CR 58 39881364
2017 HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators. Cell death & disease 56 28981088
2024 The heat shock factor 20-HSF4-cellulose synthase A2 module regulates heat stress tolerance in maize. The Plant cell 55 38573521
2006 Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts. Veterinary ophthalmology 48 16939467
2011 Familial CJD associated PrP mutants within transmembrane region induced Ctm-PrP retention in ER and triggered apoptosis by ER stress in SH-SY5Y cells. PloS one 47 21298055
2011 Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4. Oncogene 45 21258402
2008 Mutation screening of HSF4 in 150 age-related cataract patients. Molecular vision 45 18941546
2006 Novel HSF4 mutation causes congenital total white cataract in a Chinese family. American journal of ophthalmology 45 16876512
2013 HSF4 regulates DLAD expression and promotes lens de-nucleation. Biochimica et biophysica acta 44 23507146
2009 Characterization of the mineral phosphate solubilizing activity of Serratia marcescens CTM 50650 isolated from the phosphate mine of Gafsa. Archives of microbiology 38 19771411
2008 A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan. BMC medical genetics 36 19014451
1994 The catechol 2,3-dioxygenase gene of Rhodococcus rhodochrous CTM: nucleotide sequence, comparison with isofunctional dioxygenases and evidence for an active-site histidine. Microbiology (Reading, England) 35 8180697
2012 HSF4 is involved in DNA damage repair through regulation of Rad51. Biochimica et biophysica acta 30 22587838
2012 Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Molecular cancer research : MCR 29 22355043
2009 Identification of vimentin as a novel target of HSF4 in lens development and cataract by proteomic analysis. Investigative ophthalmology & visual science 29 19628735
2010 Characterization of the KRN cell transfer model of rheumatoid arthritis (KRN-CTM), a chronic yet synchronized version of the K/BxN mouse. The American journal of pathology 26 20696780
2010 DNA-binding and transcriptional activities of human HSF4 containing mutations that associate with congenital and age-related cataracts. Biochimica et biophysica acta 24 20670914
2009 Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd. Veterinary ophthalmology 24 19883468
2017 A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family. Eye (London, England) 22 29243736
2017 Closed Genome Sequence of Chryseobacterium piperi Strain CTMT/ATCC BAA-1782, a Gram-Negative Bacterium with Clostridial Neurotoxin-Like Coding Sequences. Genome announcements 21 29192076
2015 Biocontrol of tomato plant diseases caused by Fusarium solani using a new isolated Aspergillus tubingensis CTM 507 glucose oxidase. Comptes rendus biologies 21 26299190
2006 Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice. Genomics 21 16595169
1991 Degradation of 2-methylaniline and chlorinated isomers of 2-methylaniline by Rhodococcus rhodochrous strain CTM. Journal of general microbiology 21 1955877
2007 Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier. The Journal of heredity 20 17611257
2015 Hsf4 counteracts Hsf1 transcription activities and increases lens epithelial cell survival in vitro. Biochimica et biophysica acta 19 25601714
1991 Degradation of 2-methylaniline in Rhodococcus rhodochrous: cloning and expression of two clustered catechol 2,3-dioxygenase genes from strain CTM. Journal of general microbiology 19 1955878
2015 HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53. Biochimica et biophysica acta 17 25940838
2014 A novel HSF4 gene mutation causes autosomal-dominant cataracts in a Chinese family. G3 (Bethesda, Md.) 17 24637349
2015 A novel homozygous mutation in HSF4 causing autosomal recessive congenital cataract. Journal of human genetics 16 26490182
2022 HSF4 promotes tumor progression of colorectal cancer by transactivating c-MET. Molecular and cellular biochemistry 15 36229759
2013 Coexpression of the pyrroloquinoline quinone and glucose dehydrogenase genes from Serratia marcescens CTM 50650 conferred high mineral phosphate-solubilizing ability to Escherichia coli. Applied biochemistry and biotechnology 15 23737304
2013 BioBanking as the central tool for translational medicine CTM issue 2013. Clinical and translational medicine 14 23388084
2013 Functional analysis of HSF4 mutations found in patients with autosomal recessive congenital cataracts. Investigative ophthalmology & visual science 14 24045990
2022 FGD3 binds with HSF4 to suppress p65 expression and inhibit pancreatic cancer progression. Oncogene 13 34975151
2023 Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function. Journal of virology 12 37712702
2018 HSF4 transcriptional regulates HMOX-1 expression in HLECs. Gene 12 29454088
2014 HSF4 mutation p.Arg116His found in age-related cataracts and in normal populations produces childhood lamellar cataract in transgenic mice. Human mutation 12 24975927
2000 High-dose chemotherapy (CTM) for breast cancer. Bone marrow transplantation 12 10967563
2018 Novel mutations in HSF4 cause congenital cataracts in Chinese families. BMC medical genetics 11 30143024
2011 (Ctm)PrP and ER stress: a neurotoxic mechanism of some special PrP mutants. Prion 11 21795854
2008 Comparative evaluation of the COBAS AmpliPrep/COBAS TaqMan HIV type 1 test (CAP/CTM) and VERSANT HIV type 1 RNA 3.0 assay (bDNA) for quantifying HIV type 1 viral loads in China. AIDS research and human retroviruses 11 18928395
2012 Zebrafish HSF4: a novel protein that shares features of both HSF1 and HSF4 of mammals. Cell stress & chaperones 10 22528049
2006 KLF6 and HSF4 transcriptionally regulate multidrug resistance transporters during inflammation. Biochemical and biophysical research communications 10 17196161
2019 Structural analysis of missense mutations occurring in the DNA-binding domain of HSF4 associated with congenital cataracts. Journal of structural biology: X 9 32647819
2015 BCAS2 interacts with HSF4 and negatively regulates its protein stability via ubiquitination. The international journal of biochemistry & cell biology 8 26319152
2015 Performance of Roche CAP/CTM HIV-1 qualitative test version 2.0 using dried blood spots for early infant diagnosis. Journal of virological methods 8 26706730
2024 miR-330-5p Suppress Cell Growth and Invasion via Disrupting HSF4-mediated MACC1/STAT3 Pathway in Colorectal Cancer. Frontiers in bioscience (Landmark edition) 7 38420805
2015 A novel HSF4 mutation in a Chinese family with autosomal dominant congenital cataract. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 7 25877371
2012 Cell-type-dependent access of HSF1 and HSF4 to αB-crystallin promoter during heat shock. Cell stress & chaperones 7 23264262
2008 Evaluation of canine heat shock transcription factor 4 (HSF4) as a candidate gene for primary cataracts in the Dachshund and the Entlebucher Mountain dog. Veterinary ophthalmology 7 18190350
2023 HSF4 Transcriptionally Activates Autophagy by Regulating ATG9a During Lens Terminal Differentiation. Investigative ophthalmology & visual science 6 37266953
2011 Functional analysis of the Hsf4(lop11) allele responsible for cataracts in lop11 mice. Molecular vision 6 22162625
2014 Expression of the HSF4 DNA binding domain-EGFP hybrid gene recreates early childhood lamellar cataract in transgenic mice. Investigative ophthalmology & visual science 5 25168898
2023 HSF4/COIL complex-dependent R-loop mediates ultraviolet-induced inflammatory skin injury. Clinical and translational medicine 4 37461263
2019 Autosomal recessive congenital cataracts linked to HSF4 in a consanguineous Pakistani family. PloS one 4 31815953
2016 A multi-center clinical study comparing Sansure Magb and CAP/CTM HBV tests in the quantitative detection of HBV DNA. Journal of infection in developing countries 4 27482808
2023 ZNF692 Promotes the Progression of Colon Adenocarcinoma by Regulating HSF4 Expression. Iranian journal of public health 3 38435777
2020 Overproduction of Glucose Oxidase by Aspergillus tubingensis CTM 507 Randomly Obtained Mutants and Study of Its Insecticidal Activity against Ephestia kuehniella. BioMed research international 3 32596402
2013 Validation of dilution of plasma samples with phosphate buffered saline to eliminate the problem of small volumes associated with children infected with HIV-1 for viral load testing using Cobas AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0 (CAP CTM HIV v2.0). Journal of virological methods 3 24025342
2023 Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function. bioRxiv : the preprint server for biology 2 37292798
2021 A novel missense mutation in the HSF4 gene of giant pandas with senile congenital cataracts. Scientific reports 2 33686159
2020 Performance Comparison of the artus HBV QS-RGQ and the CAP/CTM HBV v2.0 Assays regarding Hepatitis B Virus DNA Quantification. BioMed research international 2 32351992
2018 Comparative performance of the Biocentric Generic Viral Load, Roche CAP/CTM v1.5, Roche CAP/CTM v2.0 and m2000 Abbott assays for quantifying HIV-1 B and non-B strains: Underestimation of some CRF02 strains. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 2 30530097
2017 Performance verification and comparison of TianLong automatic hypersensitive hepatitis B virus DNA quantification system with Roche CAP/CTM system. World journal of gastroenterology 1 29085227
2013 [Establishment of mouse lens epithelial cell lines with the genotype of Hsf4-/-]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology 1 24513006
2026 HSF4 alleviates ferroptosis in colorectal cancer through transcriptional regulation of MBOAT1/2. Functional & integrative genomics 0 41622376
2026 HSF4 promotes renal cell carcinoma progression and is associated with PI3K/Akt pathway. BMC urology 0 42185995
2025 Genetic mutation in HSF4 is associated with retinal degeneration in mice. Experimental eye research 0 40023307

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