Affinage

FOXH1

Forkhead box protein H1 · UniProt O75593

Length
365 aa
Mass
39.3 kDa
Annotated
2026-06-09
57 papers in source corpus 27 papers cited in narrative 27 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

FOXH1 (FAST-1) is a forkhead/winged-helix transcription factor that serves as the DNA-binding platform for TGF-β/Nodal/Activin signaling at mesendodermal gene enhancers, controlling early developmental patterning (PMID:9288972, PMID:10572039). Through its C-terminal Smad-interaction domain it assembles a ligand-regulated trimeric activin-responsive complex with Smad2 and Smad4, in which Smad4 stabilizes the Smad2–FOXH1 complex into an active DNA-binding factor; FOXH1 recognition of its GG/GT-containing response element is essential for complex binding and target activation (PMID:9288972, PMID:10473623, PMID:9702198). High-resolution structures show FOXH1 contacts both DNA grooves more extensively than other FOX proteins and binds nucleosomal DNA with high affinity, the structural basis of its pioneer-factor pre-occupancy of cis-regulatory modules before signaling (PMID:36435807, PMID:31582430, PMID:25359723). FOXH1 acts as a bidirectional switch: in the basal state its EH1 motif recruits Groucho/TLE co-repressors (Grg4) and it associates with HDAC1 and PRC2 to silence mesendodermal loci, and upon Nodal signaling Smad2 physically displaces Grg4 to convert the locus from repressed to active (PMID:27085753, PMID:35848281, PMID:41040321, PMID:28325473). It primes loci by recruiting SMAD3 signal-independently, with SMAD2:SMAD4 joining the preloaded SMAD3:FOXH1 complex upon signaling (PMID:31582430). In vivo FOXH1 is required to pattern the anterior primitive streak, form the node, notochord and definitive endoderm, orient the anterior-posterior axis, and specify the anterior heart field, acting upstream of Foxa2 and directly regulating Nodal (via an autoregulatory ASE enhancer), Mef2c, Mixl1, Lim-1, and retinoic-acid synthesis genes, in cooperation with Nkx2-5, Goosecoid, Eomesodermin, PouV, and β-catenin (PMID:11358868, PMID:11358869, PMID:12091315, PMID:15363409, PMID:17568773, PMID:21637786, PMID:32650116). Beyond development, FOXH1 directly represses androgen and estrogen receptor transactivation through protein-protein interaction (PMID:16120611, PMID:19711044) and is a required mediator of gain-of-function mutant p53 activity sustaining self-renewal in complex-karyotype AML (PMID:31068365).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Established the founding mechanism: how an Activin/TGF-β signal is converted into a DNA-binding transcriptional output, by showing FOXH1 nucleates a ligand-regulated Smad2/Smad4 complex.

    Evidence Co-IP, yeast two-hybrid, deletion mutagenesis and dominant-negative overexpression defining the C-terminal Smad2-interaction domain and Smad4-dependent stabilization

    PMID:9288972

    Open questions at the time
    • Did not define the DNA motif or genomic targets
    • Structural basis of the Smad interaction not resolved
  2. 1998 High

    Defined the cis-regulatory logic: FOXH1 recognizes a specific DNA motif but requires an adjacent Smad-binding element and endogenous Smad4 for ligand-dependent activation, explaining combinatorial specificity.

    Evidence Reporter assays, DNA-binding assays, Co-IP and Smad4-null cell complementation for human FOXH1; Co-IP and reporter assays for mouse Fast1

    PMID:10349617 PMID:9702198

    Open questions at the time
    • Did not resolve whether FOXH1 or Smad binding dominates complex assembly
    • No in vivo loss-of-function
  3. 1999 High

    Placed FOXH1 as a required effector of TGF-β-superfamily-induced mesoderm/endoderm formation and dissected the contribution of each DNA-binding component to the response.

    Evidence Dominant-active/negative and repressor-fusion overexpression plus blocking antibody in Xenopus; in vitro reconstitution with mutagenic in vivo reporters

    PMID:10473623 PMID:10572039

    Open questions at the time
    • Direct endogenous target genes not yet identified
    • Genetic null phenotype in mammals not yet known
  4. 2001 High

    Genetic knockouts established the developmental necessity of FOXH1 for Nodal signaling, node/streak formation and AP patterning, and ordered it upstream of Foxa2.

    Evidence Mouse targeted knockout, genetic epistasis with nodal, tissue-specific rescue, and marker (Foxa2) expression analysis; two independent labs

    PMID:11358868 PMID:11358869

    Open questions at the time
    • Did not separate signaling-dependent from signaling-independent FOXH1 functions
    • AVE formation shown to be FOXH1-independent, leaving that pathway unexplained
  5. 2002 High

    Identified direct enhancer targets and an autoregulatory loop, showing FOXH1 controls Nodal's own intronic ASE enhancer and the Lim-1 intron, establishing feedback architecture.

    Evidence Targeted intronic enhancer deletion in mouse and reporter/mutagenesis assays across species

    PMID:12091315 PMID:12454922

    Open questions at the time
    • Did not address co-factor recruitment at these enhancers
    • Mechanism of left-right asymmetry contribution incomplete
  6. 2004 High

    Revealed context-specific partnerships and Smad-independent functions: FOXH1 cooperates with Nkx2-5 to specify the anterior heart field and with β-catenin/Tcf3 to regulate Xnr genes without Smad2.

    Evidence Mouse knockout, Co-IP (FOXH1-Nkx2-5), AHF reporter/transgenic assays; maternal depletion and co-injection epistasis in Xenopus

    PMID:15363409 PMID:15459100

    Open questions at the time
    • Molecular basis of Smad-independent activation not defined
    • Generality of context-dependent partners across tissues unknown
  7. 2005 Medium

    Extended FOXH1 to nuclear-receptor repression and mapped its Smad-interaction motif as a druggable interface inhibiting TGF-β signaling.

    Evidence AR reporter assays, Co-IP and confocal foci analysis; Smad-binding peptide aptamer (Trx-xFoxH1b) GST pulldown, Co-IP and reporter inhibition

    PMID:15750622 PMID:16120611

    Open questions at the time
    • AR repression shown in reporter/cell systems only, no in vivo confirmation
    • Physiological relevance of AR/FoxH1 cross-talk unestablished
  8. 2007 High

    Defined an active repressive role: FOXH1 recruits Goosecoid and HDACs to silence Mixl1, showing FOXH1 is not solely an activator.

    Evidence Mouse knockout (expanded Mixl1), Co-IP (FOXH1-Gsc), HDAC recruitment and embryoid-body rescue

    PMID:17568773

    Open questions at the time
    • Did not establish how the switch between activation and Gsc-mediated repression is controlled
    • HDAC identity at the locus not specified
  9. 2008 Medium

    Genome-scale enhancer mapping linked FOXH1 directly to retinoic-acid synthesis and forebrain patterning genes, broadening its target repertoire beyond classic mesendoderm.

    Evidence Genome-wide Smad/Foxh1 enhancer (SFE) mapping with in situ validation in mutants and an RA-responsive transgenic reporter

    PMID:18331719

    Open questions at the time
    • Direct binding at each locus not individually validated
    • Single lab
  10. 2016 High

    Resolved the molecular switch mechanism: the EH1 motif binds Grg4/Groucho for repression, and Smad2 physically displaces Grg4 upon Nodal signaling to activate the same enhancer.

    Evidence ChIP of FoxH1 and Grg4 occupancy at the Xnr1 enhancer, EH1 point mutagenesis, and a Smad-binding-deficient mutant

    PMID:27085753

    Open questions at the time
    • Kinetics of the co-repressor-to-co-activator exchange not quantified
    • Whether HDAC/PRC2 recruitment occurs through the same EH1 interface unresolved
  11. 2017 Medium

    Demonstrated pioneer-factor behavior in vivo: FOXH1 pre-occupies CRMs before signaling, recruits Tle/Groucho, marks enhancers with H3K4me1/Ep300, and hands off to zygotic Foxa.

    Evidence Multi-stage ChIP-seq of Foxh1, Tle, H3K4me1 and Ep300 with genome-wide CRM analysis

    PMID:25359723 PMID:28325473

    Open questions at the time
    • The maternal-to-zygotic hand-off not validated by mutagenesis
    • Determinants of which pre-bound CRMs become active vs silenced unclear
  12. 2019 High

    Provided structural and biochemical proof of distinct SMAD2 vs SMAD3 roles, defining a signal-independent SMAD3:FOXH1 priming step and a signal-driven SMAD2:SMAD4 activation step.

    Evidence Crystal/structural analysis of SMAD2 E3-insert conformation, biochemical DNA-binding, ChIP-seq in mesendoderm precursors and subcellular fractionation

    PMID:31582430

    Open questions at the time
    • How SMAD3:FOXH1 priming is established without ligand at the chromatin level not fully resolved
    • Functional consequence of priming for transcription output not quantified
  13. 2019 Medium

    Expanded FOXH1 into disease and reprogramming biology, showing it is a required effector of gain-of-function mutant p53 self-renewal in AML and a pro-epithelial mediator during somatic reprogramming.

    Evidence ChIP-seq co-occupancy and genetic depletion in a mouse leukemia model; siRNA/overexpression and reprogramming-efficiency assays with NANOG/LIN28/DOT1L

    PMID:31068365 PMID:31712708

    Open questions at the time
    • Mechanism linking mutant p53 to FOXH1 transcription incompletely defined
    • Reprogramming role rests on knockdown/expression readouts only (Low confidence)
  14. 2022 High

    Established the structural basis of GG/GT-motif and nucleosome recognition and identified the PRC2/HDAC1 repressive interactome, unifying DNA-binding specificity with the silencing arm of FOXH1 function.

    Evidence Multiple FoxH1-DNA crystal structures with nucleosome-binding assays; proteomic interactome in mESCs with Co-IP and Xenopus reporter validation

    PMID:35848281 PMID:36435807

    Open questions at the time
    • Whether nucleosome binding actively opens chromatin not directly tested
    • How PRC2/HDAC1 recruitment is balanced against Smad activation unresolved
  15. 2020 Medium

    Defined coherent feedforward integration with the Wnt/β-catenin pathway, showing FOXH1 pre-binding overlaps β-catenin regions and is required for maternal Wnt target expression.

    Evidence β-catenin ChIP-seq, RNA-seq and Foxh1/Nodal loss-of-function in early embryos

    PMID:32650116

    Open questions at the time
    • Direct physical interaction with β-catenin not demonstrated
    • Single lab
  16. 2025 Medium

    Showed FOXH1 directly recruits the PRC2 catalytic subunit Ezh2 to its loci during zygotic genome activation, mechanistically grounding its dual activator/silencer role.

    Evidence Maternal Foxh1-null embryos with Ezh2 and H3K27me3 ChIP-seq and Co-IP (preprint)

    PMID:41040321

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Direct Ezh2-FOXH1 interaction interface not mapped
    • How the same factor selects activation vs PRC2 silencing per cell type unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular cues determine, at a given pre-bound locus and cell type, whether FOXH1 recruits co-repressors (Groucho/HDAC1/PRC2) for silencing versus Smad complexes for activation.
  • No single-locus model integrating co-repressor exchange, SMAD2/3 priming, and PRC2 recruitment
  • Cell-type determinants of the activation/repression switch unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140110 transcription regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
EZH2GSCHDAC1NKX2-5SMAD2SMAD3SMAD4TLE/GRG4
Complex memberships
PRC2activin-responsive factor (FOXH1-Smad2-Smad4)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 FOXH1 (FAST-1) forms a trimeric activin-responsive factor (ARF) complex with Smad2 and Smad4 in a ligand-regulated fashion. The C-terminal domain of FAST-1 interacts with Smad2 (but not Smad4) in a yeast two-hybrid assay; Smad4 stabilizes the ligand-stimulated Smad2-FAST-1 complex as an active DNA-binding factor. Overexpression of the FAST-1 C-terminal domain specifically inhibits activin signaling. Co-immunoprecipitation, yeast two-hybrid assay, deletion mutagenesis, dominant-negative overexpression Nature High 9288972
1998 Human FOXH1 (hFAST-1) binds Smad2 and activates an activin response element (ARE) containing the DNA motif TGT(G/T)(T/G)ATT. hFAST-1-dependent activation of ARE requires endogenous Smad4 and a TGF-β-like ligand. A single copy of the FOXH1 DNA motif activates a reporter in a TGF-β-dependent fashion only when an adjacent Smad-binding element is present. Reporter assay, DNA binding assay, co-immunoprecipitation, Smad4-null cell complementation Molecular cell High 9702198
1998 Mouse Fast1 (Foxh1) associates with Smads in response to activin/TGF-β signal to form a complex that recognizes the Xenopus ARE. Introduction of Fast1 into intact cells confers activin/TGF-β regulation of an ARE-luciferase reporter. Co-immunoprecipitation, luciferase reporter assay, in vitro binding assay Mechanisms of development Medium 10349617
1999 FAST-1 is a key mediator of mesoderm induction by TGF-β superfamily ligands: constitutively active FAST-VP16 induces mesodermal and endodermal genes in ectoderm and secondary axes; a FAST-1 repressor fusion (FAST-En(R)) blocks mesodermal gene induction by activin; a blocking antibody against FAST-1 prevents induction of mesodermal genes by activin or Vg1 but not FGF. Dominant-active and dominant-negative overexpression in Xenopus embryos, blocking antibody injection, gene expression analysis Development (Cambridge, England) High 10572039
1999 ARF (containing FAST-1/Smad2/Smad4) binds the ARE through both FAST-1 and Smad DNA-binding sites. FAST-1 recognition of the ARE is essential for ARF binding and activin regulation in vivo; Smad binding enhances but is not required for ARF binding or regulation. Smad3 can partially substitute for Smad4 in ARE regulation. In vitro binding assays, deletion/mutation reporter assays in Xenopus embryos The Journal of biological chemistry High 10473623
2001 FoxH1-deficient mice recapitulate Nodal signaling loss phenotypes including failed anterior-posterior axis orientation and absence of the definitive node. Heterozygosity for nodal worsens FoxH1-/- phenotype, demonstrating genetic interaction between FoxH1 and nodal. FoxH1 expression in primitive endoderm rescues A-P patterning defects but not midline defects. Targeted gene knockout in mouse, genetic epistasis (FoxH1-/-;nodal heterozygous compound mutants), tissue-specific rescue transgene Genes & development High 11358868
2001 FoxH1 deletion in mice causes failure to pattern the anterior primitive streak and form node, prechordal mesoderm, notochord, and definitive endoderm; AVE formation is FoxH1-independent. Foxa2 expression is dependent on FoxH1 function, placing FoxH1 upstream of Foxa2 in the activin/nodal-Smad pathway. Targeted gene knockout in mouse, in situ hybridization for Foxa2 expression, genetic pathway analysis Genes & development High 11358869
2002 A conserved intronic enhancer (ASE) containing FoxH1 binding sites controls Nodal expression in epiblast and visceral endoderm. ASE activity is strictly Foxh1-dependent: removal of the ASE eliminates transcription in visceral endoderm, decreases Nodal in epiblast, disrupts AP axis orientation, reduces left-sided Nodal expression, and delays Pitx2 expression. This establishes a Nodal-FoxH1 autoregulatory feedback loop. Targeted deletion of intronic enhancer in mouse, reporter assays, in situ hybridization Development (Cambridge, England) High 12091315
2002 Regulation of the Lim-1 (Xlim-1) gene by activin/nodal depends on a cluster of FAST-1/FoxH1 and Smad4 recognition sites in the first intron. Mutation of FAST-1/FoxH1 sites or use of dominant-negative FAST-1/FoxH1 chimeras abolishes activin-dependent reporter activity. FoxH1 sites in zebrafish lim1 first intron also mediate FoxH1-dependent regulation. Reporter constructs with mutated FAST-1/FoxH1 sites, dominant-negative FoxH1 chimeras, cross-species comparative analysis Developmental dynamics Medium 12454922
2004 Foxh1 is essential for development of the anterior heart field (AHF): Foxh1-/- embryos fail to form the outflow tract and right ventricle. Mef2c is a direct transcriptional target of Foxh1; Foxh1 physically and functionally interacts with Nkx2-5 to mediate Smad-dependent activation of a TGF-β response element in the Mef2c gene that directs expression to the AHF. Mouse knockout, co-immunoprecipitation (Foxh1-Nkx2-5 interaction), reporter assays with TGF-β response element, transgenic reporter in AHF territory Developmental cell High 15363409
2004 In Xenopus, maternal FoxH1 is required together with XTcf3/β-catenin to activate zygotic Xnr3 expression in a Smad2-independent manner. Maternal FoxH1 also acts as an inhibitor of Xnr5 and Xnr6 transcription, preventing their upregulation on the ventral side by the maternal T-box factor VegT. These roles are context-dependent and distinct from the ARF complex function. Maternal mRNA depletion (antisense), co-injection experiments with XTcf3/β-catenin, in situ hybridization for nodal gene expression Development (Cambridge, England) Medium 15459100
2005 FoxH1 represses both ligand-dependent and -independent transactivation of the androgen receptor (AR) independently of its own transactivation capacity and activin A. A direct protein-protein interaction was identified between AR and FoxH1 independently of dihydrotestosterone. FoxH1 specifically blocks foci formation of dihydrotestosterone-activated AR in the nucleus; Smad2/Smad4 relieves FoxH1-mediated AR repression. Reporter assay (AR-responsive promoters), co-immunoprecipitation, confocal microscopy of nuclear foci The Journal of biological chemistry Medium 16120611
2005 A Smad-binding peptide aptamer derived from the FoxH1 Smad-interaction motif (Trx-xFoxH1b) selectively inhibits TGF-β-induced expression from the FoxH1-Smad-dependent reporter A3-lux (~50% inhibition) and partially inhibits other TGF-β-responsive reporters. The aptamer binds Smads by GST pulldown and co-immunoprecipitation. GST pulldown, co-immunoprecipitation, luciferase reporter assay with seven TGF-β-responsive reporters Oncogene Medium 15750622
2007 Foxh1 recruits the homeodomain protein Goosecoid (Gsc) to form a DNA-binding repressor complex; Gsc in turn recruits histone deacetylases to repress Mixl1 gene expression. Foxh1-null embryos show expanded Mixl1 expression, demonstrating Foxh1 negatively regulates Mixl1 in vivo. Gsc-mediated repression of Mixl1 is dependent on Foxh1 in embryoid bodies. Mouse knockout analysis, co-immunoprecipitation (Foxh1-Gsc), embryoid body overexpression, HDAC recruitment assay The EMBO journal High 17568773
2008 Foxh1 directly regulates expression of members of the Aldh1a subfamily (Aldh1a1, -2, -3), Hesx1, Lgr4, Lmo1, and Fgf8 in the developing anterior neuroectoderm. In Foxh1 mutants, expression of Aldh1a1, -2, and -3 and activation of a retinoic acid-responsive reporter is abolished in anterior structures, establishing Foxh1 as a direct regulator of retinoic acid synthesis in the forebrain. Genome-wide SFE (Smad/Foxh1 enhancer) mapping combined with Site Search bioinformatics, in situ hybridization in Foxh1 mutants, RA-responsive transgenic reporter Developmental cell Medium 18331719
2009 PKA activation increases the protein stability of FoxH1. FoxH1 inhibits PKA-induced and estradiol-induced activation of an estrogen response element (ERE). FoxH1 knockdown in MCF7 cells increases PKA-induced and estradiol-induced ERE activation, indicating FoxH1 functions as a negative regulator of ERα transcriptional activity downstream of PKA. Luciferase reporter assay, Western blot (protein stability), siRNA knockdown, MCF7 cell model Molecules and cells Low 19711044
2011 A C-terminally truncated FoxH1 protein (midway allele) lacking the Smad-interaction domain but retaining DNA-binding capability more accurately represents complete loss of FoxH1-dependent Nodal signaling than the schmalspur allele. The T-box transcription factor Eomesodermin accounts for FoxH1-independent mesendoderm specification (endoderm and non-axial mesoderm); inhibition of Eomesodermin in midway mutants phenocopies complete loss of Nodal signaling. Novel zebrafish mutant characterization, gel shift assays, Nodal overexpression epistasis, genetic double mutant analysis PLoS genetics High 21637786
2014 Foxh1 pre-occupies cis-regulatory modules (CRMs) genome-wide, cooperating with Smad2/3 during mesendoderm specification. ChIP-seq and RNA-seq in Foxh1 and Nodal loss-of-function Xenopus embryos identify a comprehensive set of direct Nodal target genes co-regulated by Foxh1-Smad2/3. Foxh1 also regulates gene expression independently of Nodal signaling and interacts with PouV in a conserved manner. ChIP-seq (Foxh1 and Smad2/3), RNA-seq on loss-of-function embryos Development (Cambridge, England) Medium 25359723
2016 FoxH1 mediates a transcriptional switch at Nodal target loci via its conserved engrailed homology-1 (EH1) motif: the EH1 motif directly binds Grg4 (a Groucho corepressor), enabling repression. Upon Nodal activation, Smad2 physically displaces Grg4 from the FoxH1-Grg4 complex at the Xnr1 enhancer (shown by ChIP), switching the locus from repressed to activated state. FoxH1 unable to bind Smad2 retains Grg4 at the enhancer even in the presence of Nodal signaling. ChIP assays (Foxh1 and Grg4 occupancy at Xnr1 enhancer), EH1 point mutagenesis, gene expression assays, protein-protein interaction Developmental biology High 27085753
2017 Foxh1 occupies cis-regulatory modules (CRMs) during cleavage stages (before Nodal signaling) and recruits the co-repressor Tle/Groucho in the early blastula. CRMs continuously occupied by Foxh1 are marked by H3K4me1 and Ep300. A molecular 'hand-off' from maternal Foxh1 to zygotic Foxa at CRMs maintains enhancer activation during mesendodermal specification. ChIP-seq (Foxh1, Tle/Groucho, H3K4me1, Ep300) at multiple developmental stages, genome-wide CRM analysis Developmental cell Medium 28325473
2019 FOXH1 is a critical mediator of gain-of-function mutant p53 (GOF Trp53) activity in complex karyotype AML: mutant p53 binds to and regulates FOXH1, and FOXH1 binds to stem cell-associated gene loci to promote aberrant self-renewal. FOXH1 is required for GOF mutant p53-driven leukemia maintenance. ChIP-seq (mutant p53 and FOXH1 genome occupancy), genetic rescue/depletion in mouse leukemia model, gene expression analysis Cancer discovery Medium 31068365
2019 FOXH1 functions as a pioneer factor with distinct roles for SMAD2 and SMAD3: FOXH1 is pre-bound to target sites and recruits SMAD3 independently of TGF-β signals, while SMAD2 remains predominantly cytoplasmic at baseline and is recruited to SMAD3:FOXH1-preloaded promoters upon Nodal signaling. Structural evidence shows SMAD2 can bind DNA via conformational change of the E3 insert. This defines a signal-independent priming step (SMAD3:FOXH1) and a signal-driven activation step (SMAD2:SMAD4 joining preloaded SMAD3:FOXH1). Crystal/structural analysis, biochemical DNA-binding assays, ChIP-seq in mouse mesendoderm precursors, subcellular fractionation Genes & development High 31582430
2019 NANOG and LIN28 co-stimulate FOXH1 expression during reprogramming; FOXH1 in turn enhances epithelial marker expression and suppresses mesenchymal gene expression in OSKM-mediated reprogramming. Blocking endogenous FOXH1 eliminates the enhanced reprogramming effect by NANOG/LIN28 and DOT1L inhibition. H3K79 methyltransferase DOT1L inhibition stimulates FOXH1 expression. siRNA knockdown, overexpression, gene expression analysis, reprogramming efficiency assays (TRA-1-60 positivity) Scientific reports Low 31712708
2020 Foxh1 pre-binding to enhancers overlaps with β-catenin association regions; direct maternal Wnt target gene expression requires Foxh1 function and Nodal/TGFβ signaling, defining a coherent feedforward co-regulation mechanism between Wnt/β-catenin and Foxh1/Nodal pathways in early embryogenesis. ChIP-seq (β-catenin), RNA-seq, loss-of-function (Foxh1 and Nodal pathway perturbation) iScience Medium 32650116
2022 High-resolution crystal structures of FoxH1 from human, frog, and fish bound to four distinct GG/GT-containing DNA sequences reveal that FoxH1 contacts both the minor and major DNA grooves, making interactions approximately twice as extensive as other FOX family members. Two specific amino acid changes account for recognition of GG/GT motifs. FoxH1 binds nucleosomal DNA with higher affinity than linear DNA, consistent with pioneer factor activity. X-ray crystallography (multiple FoxH1-DNA complex structures), nucleosome-binding assay, sequence comparison/mutagenesis Nature communications High 36435807
2022 Proteomic interactome analysis identifies FOXH1 interaction with PRC2 subunits and HDAC1 in mouse embryonic stem cells. Foxh1 physically interacts with Hdac1, and confers transcriptional repression of mesendodermal genes in Xenopus ectoderm. Proteomic pulldown (FOXH1 bait in mESCs), co-immunoprecipitation (Foxh1-Hdac1), reporter/gene expression assay in Xenopus Development, growth & differentiation Medium 35848281
2025 Foxh1 directly recruits Ezh2 (the catalytic subunit of PRC2) to Foxh1-bound genomic loci during zygotic genome activation in Xenopus. Loss of maternal Foxh1 impairs Ezh2 recruitment and causes a global reduction in H3K27me3. Foxh1 thus has a dual function: activating endodermal genes in endoderm while recruiting PRC2 to silence those same genes in ectoderm. Maternal Foxh1-null embryos, ChIP-seq (Ezh2 and H3K27me3), co-immunoprecipitation bioRxivpreprint Medium 41040321

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 496 9288972
1998 Characterization of human FAST-1, a TGF beta and activin signal transducer. Molecular cell 213 9702198
2002 The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development (Cambridge, England) 189 12091315
2001 The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes & development 184 11358868
2001 FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes & development 180 11358869
2004 Foxh1 is essential for development of the anterior heart field. Developmental cell 142 15363409
2000 The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Current biology : CB 131 10996071
2008 Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. American journal of human genetics 122 18538293
1999 FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. Development (Cambridge, England) 104 10572039
2000 Fast1 is required for the development of dorsal axial structures in zebrafish. Current biology : CB 98 10996072
1999 The role of FAST-1 and Smads in transcriptional regulation by activin during early Xenopus embryogenesis. The Journal of biological chemistry 96 10473623
2010 Integrative genomic analyses of CXCR4: transcriptional regulation of CXCR4 based on TGFbeta, Nodal, Activin signaling and POU5F1, FOXA2, FOXC2, FOXH1, SOX17, and GFI1 transcription factors. International journal of oncology 81 20043076
2019 A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1. Cancer discovery 79 31068365
2019 Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling. Genes & development 79 31582430
2001 The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling. Molecular and cellular endocrinology 78 11451566
1998 A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is expressed during early embryogenesis. Mechanisms of development 73 10349617
2017 Foxh1 Occupies cis-Regulatory Modules Prior to Dynamic Transcription Factor Interactions Controlling the Mesendoderm Gene Program. Developmental cell 64 28325473
2014 Genome-wide view of TGFβ/Foxh1 regulation of the early mesendoderm program. Development (Cambridge, England) 59 25359723
2004 New roles for FoxH1 in patterning the early embryo. Development (Cambridge, England) 56 15459100
2013 Integration of nodal and BMP signals in the heart requires FoxH1 to create left-right differences in cell migration rates that direct cardiac asymmetry. PLoS genetics 53 23358434
2005 Selective inhibition of TGF-beta responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1 and CBP. Oncogene 51 15750622
2008 Genome-wide identification of Smad/Foxh1 targets reveals a role for Foxh1 in retinoic acid regulation and forebrain development. Developmental cell 50 18331719
2011 Nodal-dependent mesendoderm specification requires the combinatorial activities of FoxH1 and Eomesodermin. PLoS genetics 45 21637786
2003 Mixer/Bon and FoxH1/Sur have overlapping and divergent roles in Nodal signaling and mesendoderm induction. Development (Cambridge, England) 44 14522874
2007 An early requirement for maternal FoxH1 during zebrafish gastrulation. Developmental biology 42 17719025
2005 Modulation of androgen receptor transactivation by FoxH1. A newly identified androgen receptor corepressor. The Journal of biological chemistry 37 16120611
2014 Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial. Clinical and experimental immunology 36 24749847
2007 Foxh1 recruits Gsc to negatively regulate Mixl1 expression during early mouse development. The EMBO journal 32 17568773
2002 Regulation of the Lim-1 gene is mediated through conserved FAST-1/FoxH1 sites in the first intron. Developmental dynamics : an official publication of the American Association of Anatomists 29 12454922
2015 Benzyl isothiocyanate inhibits breast cancer cell tumorigenesis via repression of the FoxH1-Mediated Wnt/β-catenin pathway. International journal of clinical and experimental medicine 24 26770350
2005 Transcriptional regulation of the homeobox gene Mixl1 by TGF-beta and FoxH1. Biochemical and biophysical research communications 21 15982639
2021 FOXH1 promotes lung cancer progression by activating the Wnt/β-catenin signaling pathway. Cancer cell international 20 34090445
2019 FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming. Scientific reports 16 31712708
2022 Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1. Nature communications 15 36435807
2020 Foxh1/Nodal Defines Context-Specific Direct Maternal Wnt/β-Catenin Target Gene Regulation in Early Development. iScience 15 32650116
2009 Forkhead box H1 (FOXH1) sequence variants in ventricular septal defect. International journal of cardiology 13 19525021
2009 Foxh1 and Foxa2 are not required for formation of the midgut and hindgut definitive endoderm. Developmental biology 13 19896480
2016 FoxH1 mediates a Grg4 and Smad2 dependent transcriptional switch in Nodal signaling during Xenopus mesoderm development. Developmental biology 12 27085753
2009 PKA-mediated stabilization of FoxH1 negatively regulates ERalpha activity. Molecules and cells 11 19711044
2020 Homozygous mutation of foxh1 arrests oogenesis causing infertility in female Nile tilapia†. Biology of reproduction 10 31837141
2021 Large-scale whole-exome sequencing association study identifies FOXH1 gene and sphingolipid metabolism pathway influencing major depressive disorder. CNS neuroscience & therapeutics 9 34633764
2018 FAST-1 antisense RNA epigenetically alters FXN expression. Scientific reports 9 30464193
2019 FoxH1 represses miR-430 during early embryonic development of zebrafish via non-canonical regulation. BMC biology 8 31362746
2018 FAST1 promotes the migration and invasion of colorectal cancer cells. Biochemical and biophysical research communications 7 30594391
2014 Disrupting Foxh1-Groucho interaction reveals robustness of nodal-based embryonic patterning. Mechanisms of development 6 25511461
2024 HTR3A Promotes Non-small Cell Lung Cancer Through the FOXH1/Wnt3A Signaling Pathway. Biochemical genetics 5 39046651
2022 A comprehensive analysis of FOX family in HCC and experimental evidence to support the oncogenic role of FOXH1. Aging 5 35255005
2020 Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect. Clinical genetics 4 32003456
2024 Olanzapine enhances early brain maturation through activation of the NODAL/FOXH1 axis. iScience 3 39474064
2005 Expression of the FAST-1 transcription factor in coronary artery transplant vasculopathy and activated vascular smooth muscle cells. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 3 15737749
2025 CRISPR Screening Reveals a Novel Role for FOXH1 in Regulating Pluripotency of Porcine Embryonic Stem Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 40641457
2024 Smad4 and FoxH1 potentially interact to regulate cyp19a1a promoter in the ovary of ricefield eel (Monopterus albus). Biology of sex differences 2 39080808
2022 Engagement of Foxh1 in chromatin regulation revealed by protein interactome analyses. Development, growth & differentiation 2 35848281
2020 Generation of a FOXH1 homozygous knockout human embryonic stem cell line by CRISPR/Cas9 system. Stem cell research 2 33348200
2023 FoxH1 Represses the Promoter Activity of cyp19a1a in the Ricefield Eel (Monopterus albus). International journal of molecular sciences 1 37762014
2026 Phenylephrine attenuates LPS-induced lung injury via Foxh1/GSK-3β/β-catenin-mediated alveolar epithelial cell differentiation in ARDS. International immunopharmacology 0 41865454
2025 Foxh1 is a locus-specific PRC2 recruiter governing germ layer silencing. bioRxiv : the preprint server for biology 0 41040321

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