Affinage

HHEX

Hematopoietically-expressed homeobox protein HHEX · UniProt Q03014

Length
270 aa
Mass
30.0 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HHEX (Hex/PRH) is a divergent homeodomain transcription factor that functions predominantly as a sequence-specific transcriptional repressor, acting through a proline-rich N-terminal repression domain that is separable from the DNA-binding homeodomain; fusing this domain to a heterologous activation domain converts it to an activator, establishing its intrinsic repressive nature (PMID:10804173, PMID:10085234). Repression is executed by recruiting Groucho/TLE co-repressors through an Eh-1 motif, with simultaneous DNA and TLE binding required to retain TLE in subnuclear domains (PMID:18713067). Through this machinery HHEX directly binds and represses a coherent set of angiogenic and developmental targets—VEGF, VEGFR-1, and VEGFR-2 (PMID:20176809), ESM-1 (PMID:16764824), Vegfa during cardiac cushion EMT (PMID:15459110), EOMES (PMID:24651531), and pdx1/cdx1b (PMID:30428031)—and can also activate genes such as Endoglin to restrain tumor cell migration (PMID:24240683). A unifying theme is the control of organ progenitor identity and positioning in definitive endoderm: HHEX is required cell-autonomously for liver bud morphogenesis and hepatoblast pseudostratification (PMID:10804184, PMID:11027604, PMID:16364283), acts upstream of HNF4α/HNF6/HNF1β in hepatobiliary morphogenesis (PMID:17580084), gates pancreatic lineage commitment by restraining FOXA1/2 and GATA4 from alternative fates (PMID:35787684), and specifies islet δ cells (PMID:24736842). HHEX is governed post-translationally by CK2 phosphorylation, which inhibits DNA binding and triggers proteasomal cleavage to a dominant-negative fragment that de-represses VEGFR-1 (PMID:22844093), and operates combinatorially with partners including GATA factors (PMID:15016828), c-Myc (PMID:25220416), SOX13 (PMID:20028982), and TEAD4 (PMID:36008411). In hematopoiesis and immunity it promotes hemangioblast and B-cell development (PMID:12791650, PMID:12522149), drives memory B-cell differentiation with TLE3 (PMID:32601467), and represses Foxp3 to restrain Treg function (PMID:31792183). In cancer HHEX behaves context-dependently, repressing Cdkn2a via direct PRC2 recruitment to sustain MLL-rearranged AML (PMID:26728554) while suppressing proliferation of hepatocellular and epithelial tumors (PMID:25220416, PMID:24240683).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 Medium

    Establishing the molecular identity of HHEX defined it as a single-copy homeodomain gene with lineage-restricted hematopoietic expression, providing the entry point for all subsequent functional work.

    Evidence cDNA cloning and expression profiling in human hematopoietic cells and lines

    PMID:8096636

    Open questions at the time
    • No biochemical activity assigned at cloning
    • DNA-binding specificity and target genes unknown
  2. 2000 High

    Domain mapping resolved how HHEX acts on DNA, showing the homeodomain mediates DNA binding while a separable proline-rich N-terminal domain confers transcriptional repression that converts to activation when fused to VP16.

    Evidence GAL4-fusion reporter assays with deletion mutagenesis plus Xenopus gain/loss-of-function

    PMID:10085234 PMID:10804173

    Open questions at the time
    • Co-repressor identity not yet defined
    • Direct genomic targets in vivo not mapped
  3. 2000 High

    Knockouts and chimeric analysis defined the cell-autonomous requirement for HHEX in definitive endoderm for forebrain, liver, and thyroid organogenesis, moving it from an expression marker to a developmental driver.

    Evidence Homologous-recombination knockout mice, chimeric embryo analysis, histology

    PMID:10804184 PMID:11027604

    Open questions at the time
    • Downstream transcriptional targets in endoderm not identified
    • Molecular basis of migration failure unresolved
  4. 2003 Medium

    Endothelial overexpression and B-cell complementation studies established HHEX as a negative regulator of angiogenic receptor programs and as a requirement for B-lineage development, broadening its role beyond early endoderm.

    Evidence HUVEC overexpression with microarray/RT-PCR and RAG1-deficient blastocyst complementation

    PMID:12522149 PMID:12588764

    Open questions at the time
    • Direct versus indirect repression of receptor genes not distinguished here
    • Repression mechanism not tied to a co-repressor
  5. 2004 High

    Mechanistic dissection of endoderm phenotypes and a direct GATA interaction clarified that HHEX controls progenitor positioning and proliferation and physically partners GATA factors to repress flk-1/KDR.

    Evidence Hex-null embryo analysis with endoderm explants, plus yeast two-hybrid/co-IP/EMSA and tube-formation assays

    PMID:12791650 PMID:14736744 PMID:15016828 PMID:15459110

    Open questions at the time
    • Whether GATA partnership generalizes beyond endothelium unclear
    • Positional defects not linked to specific direct targets
  6. 2006 High

    Direct-target identification (ESM-1) and Wnt/Nodal pathway epistasis showed HHEX represses defined endothelial and signaling genes through bona fide promoter occupancy and modulates Wnt and Nodal outputs in early patterning.

    Evidence ChIP/EMSA/mutagenesis on ESM-1 and Xenopus/ES-cell pathway readouts

    PMID:15687261 PMID:16364283 PMID:16764824 PMID:16936074

    Open questions at the time
    • Genome-wide target catalog still absent
    • Context determining repression versus indirect Wnt amplification unresolved
  7. 2009 Medium

    The co-repressor mechanism was defined: HHEX recruits and nuclear-retains Groucho/TLE via an Eh-1 motif, requiring simultaneous DNA and TLE binding, explaining how its N-terminal domain enacts repression.

    Evidence Cellular fractionation, co-IP, reporter and transdominant-negative analyses

    PMID:18713067

    Open questions at the time
    • Specific TLE family member at endogenous loci not defined
    • Structural basis of the DNA+TLE requirement unknown
  8. 2010 High

    ChIP at VEGF/VEGFR promoters linked HHEX's direct repression of angiogenic signaling to tumor and leukemic cell survival, connecting its transcriptional activity to a disease-relevant phenotype.

    Evidence ChIP, reporter assays, overexpression/knockdown with survival readouts

    PMID:20176809

    Open questions at the time
    • Causality between specific target and survival not isolated
    • Cell-type dependence not mapped
  9. 2012 High

    CK2 phosphorylation was identified as a key post-translational switch that inhibits HHEX DNA binding and generates a dominant-negative cleavage fragment, providing a mechanism for dynamic de-repression of targets like VEGFR-1.

    Evidence In vitro kinase assay, ChIP, proteasome-inhibitor and reporter experiments

    PMID:22844093

    Open questions at the time
    • Phosphosites and their individual contributions not fully resolved
    • Physiological triggers of CK2 activity on HHEX undefined here
  10. 2014 Medium

    Multiple studies expanded HHEX's regulatory repertoire to delta-cell specification, c-Myc antagonism, EOMES repression in hepatic specification, and Kit-dependent leukemic self-renewal, showing partner- and target-specific outputs across tissues.

    Evidence Conditional knockouts, co-IP, ChIP, hESC differentiation and leukemia transplantation assays

    PMID:24585688 PMID:24651531 PMID:24736842 PMID:25220416 PMID:25283843

    Open questions at the time
    • Whether common co-repressor machinery underlies these diverse targets unclear
    • Direct versus indirect effects vary by study
  11. 2017 High

    Demonstration that HHEX recruits PRC2 to the Cdkn2a locus for H3K27me3-mediated silencing established a direct epigenetic mechanism by which it sustains MLL-rearranged AML, defining a chromatin-level mode of repression.

    Evidence Conditional knockout, ChIP at Cdkn2a, co-IP with PRC2 subunits, transplantation

    PMID:26728554

    Open questions at the time
    • Generality of PRC2 recruitment to other HHEX targets untested
    • Selectivity for leukemic versus normal myelopoiesis mechanism partial
  12. 2020 High

    Immune studies defined opposing context-specific roles: HHEX cooperates with TLE3 to drive memory B-cell differentiation while directly repressing Foxp3 to restrain Treg function, unifying its dual activator/repressor behavior under partner control.

    Evidence CRISPR screening, scRNA-seq, co-IP, conditional knockout, ChIP and rescue experiments

    PMID:31792183 PMID:32601467

    Open questions at the time
    • What dictates activator versus repressor output in immune cells not fully resolved
    • TLE3 versus other co-factor usage across cell states unclear
  13. 2022 High

    CRISPR and multi-omics in human cells showed HHEX gatekeeps pancreatic commitment by restraining pioneer factors, and that CK2 phosphorylation promotes a HHEX-TEAD4 partnership stabilizing YAP-TEAD on chromatin, revealing both lineage-restriction and oncogenic co-regulatory functions.

    Evidence Human PSC CRISPR screens, single-cell/multi-omics, co-IP, ChIP, kinase assays and xenografts

    PMID:35385752 PMID:35787684 PMID:36008411

    Open questions at the time
    • How HHEX physically restrains FOXA1/2/GATA4 binding not structurally defined
    • Balance between repressive and YAP-TEAD-activating roles in tumors unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified determinant of whether HHEX represses or activates a given locus, and a genome-wide map integrating its TLE-, PRC2-, GATA-, c-Myc-, and TEAD4-dependent modes across cell types, remains undefined.
  • No comprehensive genome-wide occupancy map across tissues
  • Rules governing partner choice and activator/repressor switching unknown
  • No structural model of HHEX-co-factor complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 1
Partners
C-MYCCD81GATA2PRC2SOX13TEAD4TLE3
Complex memberships
PRC2 (HHEX-associated)YAP-TEAD complex (HHEX-stabilized)

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 HHEX (Hex/PRH) functions as a transcriptional repressor; the repression domain maps to the proline-rich N-terminal region (residues 45–136), independent of the homeodomain, while the homeodomain is responsible for DNA binding. Fusion of Hex to VP16 activation domains converts it to an activator, and over-expression of wild-type Hex causes cell-autonomous suppression of dorsal mesoderm, including down-regulation of Goosecoid and Chordin. Transient transfection experiments suggest Goosecoid is a direct target. GAL4-fusion luciferase repression assays, Xenopus gain/loss-of-function overexpression, deletion mutagenesis, ES cell co-transfection Development (Cambridge, England) / Biochemical journal High 10085234 10804173
2000 HHEX is required in definitive endoderm for normal forebrain, liver, and thyroid development. In Hex-null mice, the liver diverticulum forms but hepatocyte migration into the septum transversum fails; thyroid development arrests at the bud stage. Chimeric embryo analysis localizes the forebrain defect to Hex function in definitive endoderm (not visceral endoderm). Homologous recombination knockout, chimeric embryo analysis, histology Development (Cambridge, England) High 10804184 11027604
2004 HHEX controls the proliferation rate and positioning of leading-edge ventral-lateral endoderm cells; in Hex-null embryos endoderm fails to grow beyond cardiogenic mesoderm (a pancreas inducer inhibitor), causing complete failure of ventral pancreatic specification while liver induction is retained. Hex-null ventral endoderm isolated before contact with cardiogenic mesoderm activates early pancreas genes in vitro, confirming the defect is positional rather than a direct transcriptional block. Hex−/− mouse embryo analysis, endoderm explant culture, in vitro differentiation assay Development (Cambridge, England) High 14736744
2005 HHEX cell-autonomously promotes the transition of hepatic endoderm from columnar simple epithelium to pseudostratified epithelium with interkinetic nuclear migration (INM), enabling hepatoblast emergence into stromal environment. In Hex-null hepatic endoderm, cells survive but maintain columnar morphology and ectopically express Shh and midgut markers. Hex−/− conditional mouse knockout, histology, morphological analysis, marker expression Developmental biology High 16364283
2000 In zebrafish, hhex expression in endothelial and blood lineages is downstream of the cloche gene. Ectopic hhex expression drives premature expression of early endothelial/blood differentiation markers (fli1, flk1, gata1). hhex and scl cross-regulate each other's expression. Loss-of-function of hhex alone is not essential for early endothelial/blood differentiation, suggesting functional compensation by scl. Zebrafish cloche mutant analysis, hhex ectopic DNA injection, hhex deficiency allele analysis, in situ hybridization Development (Cambridge, England) Medium 11003831
2004 HHEX (Hex) is required for hemangioblast differentiation to definitive hematopoietic progenitors and, to a lesser extent, endothelial cells. This was established using in vitro Hex−/− ES cell differentiation, in vivo yolk sac hematopoietic progenitor assays, and chimeric mouse analysis. Hex−/− ES cell in vitro differentiation, yolk sac progenitor assay, chimeric mouse analysis Blood Medium 12791650
2005 Wnt antagonists (Dkk-1, Crescent) in Xenopus induce HHEX expression in endoderm, and HHEX is required downstream to initiate cardiogenesis non-cell-autonomously by controlling production of a diffusible heart-inducing factor. Loss of Hex function blocks both endogenous heart development and ectopic heart induction by Dkk-1; ectopic Hex induces cardiac markers non-cell-autonomously. Xenopus gain/loss-of-function, Dkk-1/Crescent injection, downstream mediator screen Genes & development Medium 15687261
2004 HHEX null mutation causes defective vasculogenesis, right ventricular hypoplasia, enlarged endocardial cushions with ventricular septal defects, outflow tract abnormalities, and aberrant compact myocardium. Cushion enlargement is due to decreased apoptosis and dysregulated epithelial-mesenchymal transformation (EMT). Vegfa levels are elevated ~3-fold in Hhex−/− hearts, and treatment with soluble sFlt-1 (VEGF inhibitor) abolishes the excessive EMT, identifying HHEX as a repressor of Vegfa levels during development. Hhex−/− mouse null mutation analysis, AV explant culture, sFlt-1 pharmacological rescue Development (Cambridge, England) High 15459110
2007 Conditional deletion of Hhex in hepatic diverticulum (Foxa3-Cre) results in a small cystic liver, loss of Hnf4α and Hnf6 expression in early hepatoblasts, absent gallbladder, and unidentifiable extrahepatic bile duct. Later conditional deletion (Alfp-Cre) causes polycystic liver disease with absent Hnf1β in biliary epithelial cells, demonstrating Hhex is required at multiple stages of hepatobiliary morphogenesis and is upstream of Hnf4α, Hnf6, and Hnf1β. Cre-loxP conditional knockout, histology, marker expression analysis Developmental biology High 17580084
2006 HHEX acts as a transcriptional repressor in Xenopus by inhibiting expression of Tle4 (a Groucho-family co-repressor), thereby amplifying canonical Wnt/β-catenin signaling and upregulating Siamois, Xnr3, Cerberus, and other anterior endodermal genes. HHEX also directly regulates Nodal-related genes Xnr1 and Xnr2 (but not Xnr5/6) in both Xenopus and mouse ES cells, explaining its ability to suppress organizer propagation. Xenopus gain/loss-of-function, ES cell gene expression, reporter assays, Wnt pathway readouts Development (Cambridge, England) Medium 16936074
2004 HHEX physically interacts with GATA transcription factors in endothelial cells (identified by yeast two-hybrid and confirmed by co-immunoprecipitation). HHEX overexpression decreases flk-1/KDR promoter activity and endogenous flk-1/KDR expression, attenuates VEGF-mediated tube formation, and inhibits GATA-2 binding to the flk-1/KDR GATA motif in EMSA. TGFβ1 increases Hex expression and mediates repression of flk-1 via inducible Hex-GATA inhibitory complexes. Yeast two-hybrid, co-immunoprecipitation, EMSA, luciferase reporter, endothelial tube formation assay, RNase protection assay The Journal of biological chemistry High 15016828
2003 HEX acts as a negative regulator of angiogenesis in endothelial cells: overexpression in HUVECs abolishes VEGF-stimulated proliferation, migration, invasion, and network formation, and represses expression of VEGFR-1, VEGFR-2, neuropilin-1, TIE-1, TIE-2, and integrin αv, while augmenting endoglin. HEX does not alter endothelial cell differentiation (VE-cadherin-positive cells unchanged in ES cell model). Transient overexpression in HUVECs, cDNA microarray, quantitative RT-PCR, Western blot, ES cell stable transfection Arteriosclerosis, thrombosis, and vascular biology Medium 12588764
2010 PRH/HHEX directly binds to promoter regions of Vegf, Vegfr-1, and Vegfr-2 genes and represses their transcription. Overexpression or knockdown of PRH directly affects survival of leukemic and tumor cells, and this is mediated through modulation of VEGF/VEGFR signaling. Chromatin immunoprecipitation, reporter assays, overexpression/knockdown with cell survival readouts Molecular and cellular biology High 20176809
2009 PRH/HHEX causes nuclear retention of Groucho/TLE co-repressor proteins. The Eh-1 motif in the PRH N-terminal repression domain mediates binding to TLE proteins; transcriptional repression and nuclear retention of TLE require PRH to bind both TLE and DNA simultaneously. A trans-dominant-negative PRH inhibits wild-type PRH by sequestering TLE to specific subnuclear domains. Cellular fractionation, co-immunoprecipitation, reporter assays, transdominant-negative analysis, subnuclear localization The Biochemical journal Medium 18713067
2012 CK2 phosphorylates PRH/HHEX, inhibiting its DNA-binding activity, decreasing its nuclear association, and inducing proteasomal cleavage to generate a stable truncated fragment PRHΔC. PRHΔC acts as a transdominant-negative by sequestering TLE co-repressors, thereby de-repressing VEGFR-1 transcription. CK2 inhibition restores PRH binding at the Vegfr-1 promoter. In vitro kinase assay, ChIP, proteasome inhibitor experiments, reporter assays, co-immunoprecipitation Nucleic acids research High 22844093
2008 In acute myeloid leukemia, expression of NUP98/HHEX fusion (containing NUP98 GFLG repeats and the HHEX homeodomain) in murine bone marrow causes aberrant self-renewal, differentiation block, and transplantable acute leukemia. The leukemogenic activity depends on both the NUP98 GFLG repeats and the HHEX homeodomain. The fusion colocalizes to nuclear foci similar to other NUP98/homeodomain fusions and deregulates common targets (Hoxa5, Hoxa9, Flt3). Retroviral transduction of bone marrow, bone marrow transplantation, gene expression profiling, mutagenesis of fusion domains Blood High 18388181
2014 Within the adult endocrine pancreas, Hhex is selectively expressed in somatostatin-secreting δ cells. Two conditional knockout models show Hhex is required for δ-cell differentiation; decreased somatostatin in Hhex-deficient islets disrupts paracrine inhibition of insulin release from β cells, identifying HHEX as the first transcriptional regulator specifically required for islet δ cells. Conditional knockout mice (two models), immunostaining, hormone measurements, islet functional assays Genes & development High 24736842
2016 HHEX is overexpressed in AML and is essential for initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis. Mechanistically, Hhex binds the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression of Cdkn2a (p16INK4a and p19ARF). Loss of Hhex de-represses Cdkn2a, causing growth arrest and myeloid differentiation. Conditional knockout, ChIP, co-immunoprecipitation with PRC2 subunits, gene expression analysis, transplantation assays Genes & development High 26728554
2018 HHEX is an upstream transcriptional regulator of VEGFC, FLT4, and PROX1 during angiogenic sprouting and lymphatic formation. Zebrafish hhex mutants fail sprouting angiogenesis from the posterior cardinal vein required for lymphangiogenesis. Tissue-specific genetic deletions in mouse and knockdowns in human endothelial cells confirm conserved function in vascular/lymphatic development. Zebrafish mutant analysis, mouse tissue-specific conditional knockout, siRNA knockdown in human endothelial cells, molecular approaches Nature communications High 30006544
2020 HHEX cooperates with the co-repressor TLE3 to promote memory B cell (MBC) differentiation. BCL-6 directly represses Hhex in GC B cells. Hhex-deficient MBCs show increased Bcl6 and reduced Bcl2 expression, and overexpression of Bcl-2 rescues MBC differentiation in Hhex-deficient cells. Hhex also induces the transcription factor Ski during MBC differentiation. Inducible CRISPR-Cas9 screening, single-cell RNA sequencing, co-immunoprecipitation, conditional knockout, Bcl-2 overexpression rescue Nature immunology High 32601467
2019 Hhex directly binds promoters of Foxp3, Il2ra, and Ctla4 to repress their transcription, thereby inhibiting regulatory T (Treg) cell differentiation and function. TGF-β/Smad3 signaling represses Hhex expression in Treg cells. The homeodomain and N-terminal repression domain of Hhex are required for inhibition of Foxp3 and Treg signature genes. Hhex-overexpressing Treg cells fail to prevent colitis in a mouse IBD model. Retroviral overexpression, ChIP, promoter reporter assays, mouse model of colitis, in vitro Treg differentiation Proceedings of the National Academy of Sciences of the United States of America High 31792183
2003 HHEX is required for B cell development: Hex−/−;RAG1−/− chimeric mice show severely reduced mature B cells, pre-B cells, and CD5+ B cells, with a 15-fold increase in B220−CD19+ cells in bone marrow. Hex-null mice fail to generate IgG responses to T cell-independent antigens, while serum IgM and T cell-dependent antibody responses are intact. RAG1-deficient blastocyst complementation, flow cytometry, antibody response assays Proceedings of the National Academy of Sciences of the United States of America Medium 12522149
2009 Hhex physically interacts with SOX13 (identified by yeast two-hybrid with N-terminal Hhex as bait in E9.5-10.5 mouse embryo library). Hhex blocks SOX13-dependent repression of Wnt/TCF signaling by displacing SOX13 from the SOX13×TCF1 complex. Electroporating Hhex de-represses Wnt/TCF pathway in ventral foregut endoderm of cultured mouse embryos treated with SOX13. Yeast two-hybrid, co-immunoprecipitation, reporter assays, mouse embryo electroporation The Journal of biological chemistry Medium 20028982
2006 Hhex is a direct transcriptional repressor of ESM-1 (endothelial cell-specific molecule 1) in endothelial cells. ESM-1 is upregulated in Hhex−/− embryos, and Hhex overexpression downregulates ESM-1. ChIP, EMSA, site-directed mutagenesis, and cotransfection assays demonstrate direct Hhex binding to an evolutionarily conserved HRE in the ESM-1 promoter. Hhex−/− embryo analysis, overexpression, cotransfection luciferase assay, EMSA, site-directed mutagenesis, ChIP Biochemical and biophysical research communications High 16764824
2000 HNF3β and GATA-4 transactivate the Hex promoter via response elements within nt −103/+22; mutation of the HNF3 element reduces promoter activity in HepG2 cells. EMSA confirmed specific transcription factor-DNA binding at these elements. These factors contribute to liver-enriched Hex expression. Luciferase reporter assays, co-transfection, EMSA, site-directed mutagenesis Gene Medium 10767553
2000 HHEX (Hex) regulates the Na+-dependent bile acid cotransporter (ntcp) promoter via a Hex response element (HRE) at nt −733/−714. A dominant-negative Hex suppresses basal activity and activation by Hex. EMSA confirmed liver nuclear protein binds the native HRE. Hex transactivation of this element requires an additional liver cell-specific factor. Luciferase reporter assays, 5'-deletion analysis, EMSA, dominant-negative Hex, co-transfection American journal of physiology. Gastrointestinal and liver physiology Medium 10915644
2003 Thyroid-specific transcription factor TTF-1 activates the Hex promoter via functionally relevant TTF-1 binding sites identified by gel-retardation and mutagenesis. Hex protein itself activates its own promoter (~4-fold in HeLa cells). TTF-1 and Hex effects are additive (6–7-fold combined), providing a mechanism for sustained Hex expression in thyroid cells. Co-transfection, luciferase reporter, gel retardation (EMSA), mutagenesis Nucleic acids research Medium 12655000
2000 HHEX is expressed in adult thyroid gland and in differentiated follicular thyroid cell lines; TSH reduces Hex expression in FRTL-5 cells. Hex represses the thyroglobulin promoter and abolishes activating effects of both TTF-1 and Pax8. DNA-binding experiments show Hex binds sequences containing 5'-TAAT-3' or 5'-CAAG-3' in the thyroglobulin promoter. RT-PCR, co-transfection luciferase assay, protein-DNA interaction (EMSA) Nucleic acids research Medium 10871399
2014 Hhex interacts directly with the bHLH/LZ domain of c-Myc. Hhex knockdown increases proliferation in hepatocellular carcinoma cells; Hhex expression reduces proliferation by increasing G1 phase length through a c-Myc-dependent mechanism. Transcriptomic analysis shows Hhex counter-regulates multiple c-Myc targets. Hhex expression causes reduced cell size, lower RNA levels, downregulation of metabolic genes, and severely reduces tumour formation in xenografts. Co-immunoprecipitation, siRNA knockdown, overexpression, cell cycle analysis, microarray, xenograft tumor assay Oncogene Medium 25220416
2013 PRH/HHEX inhibits migration and invasion of breast and prostate epithelial cells by directly activating transcription of Endoglin. ChIP shows PRH binds the Endoglin promoter in prostate and breast cells; PRH knockdown decreases Endoglin protein and increases migration; Endoglin overexpression rescues increased migration caused by PRH knockdown. ChIP, siRNA knockdown, overexpression, cell migration/invasion assays, Endoglin rescue experiments Oncogene High 24240683
2019 TGFβ signaling downregulates PRH/HHEX activity through multiple mechanisms: TGFβ increases inhibitory CK2-mediated PRH phosphorylation, pSMAD3 binds the PRH/HHEX promoter to downregulate PRH mRNA and protein, and these changes facilitate EMT (decreased E-cadherin, increased Snail). Platelet-derived TGFβ stimulates extravasation of cells with depleted PRH. PRH regulates multiple EMT and TGFβ signaling genes. siRNA knockdown, promoter reporter assay with ChIP for pSMAD3, in vitro extravasation assay, TGFβ pathway inhibition Oncogenesis Medium 32019914
2013 Hhex physically interacts with CD81 (identified by yeast two-hybrid); when GPC3 binds to CD81, CD81-Hhex binding decreases, resulting in nuclear translocation of Hhex and transcriptional repression. GPC3 transgenic mice show decreased nuclear Hhex consistent with model. This places Hhex downstream of GPC3-CD81 in regulating liver cell proliferation. Yeast two-hybrid, co-immunoprecipitation, nuclear fractionation, GPC3 transgenic mice The American journal of pathology Low 23665349
2011 A gene regulatory network controlling hhex transcription in anterior endoderm was defined: Nodal signaling directly activates hhex via FoxH1/Smad2 binding sites in the proximal −0.44 kb promoter; BMP-induced Vent1/Vent2 homeodomain repressors suppress hhex in ventral-posterior endoderm; maternal Wnt/β-catenin cooperates with Nodal indirectly through Siamois/Twin to activate hhex via homeobox sites and by inducing BMP antagonists that exclude Vents. Xenopus cis-regulatory analysis, promoter truncation reporter assays, morpholino knockdown, overexpression epistasis Developmental biology Medium 21215263
2022 CK2 phosphorylates HHEX and enhances its interaction with TEAD4. HHEX associates with and stabilizes the YAP-TEAD complex on regulatory genomic loci to co-regulate YAP/TEAD target gene expression. HHEX also indirectly regulates YAP/TAZ expression. CK2 inhibitor CX-4945 diminishes the HHEX-TEAD4 interaction and reduces YAP/TEAD target gene expression. CX-4945 synergizes with YAP-TEAD inhibitors in colorectal cancer. Co-immunoprecipitation, ChIP, in vitro kinase assay (CK2), knockdown/overexpression, tumor xenograft Nature communications High 36008411
2022 HHEX acts as a gatekeeper of pancreatic lineage specification from foregut endoderm progenitors, cooperating with pioneer transcription factors FOXA1, FOXA2, and GATA4 to promote pancreas commitment. HHEX deletion impairs pancreatic commitment and unleashes cellular plasticity toward liver and duodenum fates. HHEX restricts FOXA1/2 and GATA4 from activating alternative lineage programs. Human PSC-guided differentiation, genome-scale CRISPR-Cas9 screening, single-cell analysis, genomics, proteomics Nature cell biology High 35787684
2014 HHEX directly binds to the HHEX response element in the first intron of EOMES (eomesodermin) and represses its expression. EOMES knockdown upregulates hepatoblast markers, indicating EOMES negatively regulates hepatic specification. HHEX promotes hepatic specification from definitive endoderm by repressing EOMES. ChIP, siRNA knockdown of HHEX and EOMES, qRT-PCR in hESC-derived definitive endoderm PloS one Medium 24651531
2002 Ectopic Hex expression in T cells (via CD11a/Hex and Lck/Hex transgenes) impairs T cell maturation, demonstrating that proper T cell development requires downregulation of Hex. Hex overexpression also significantly increases myeloid progenitor cycling. T cell-specific transgenic mouse models, flow cytometry, hematopoietic progenitor proliferation assays Immunology Medium 12460189
2019 In zebrafish hhex-null mutants, the hepatopancreatic duct (HPD) system fails to develop and is replaced by an intrahepatic intestinal tube expressing intestinal marker fabp2a. Hhex normally binds promoters of pdx1 and cdx1b to repress their expression; in hhex mutants, cdx1b and pdx1 are ectopically expressed in the intrahepatic tube, and knockdown of these genes restores sox9b expression. Zebrafish hhex-null mutant, lineage tracing, chromatin immunoprecipitation (ChIP), morpholino knockdown Journal of molecular cell biology High 30428031
2014 In Lmo2-transgenic thymocytes, Hhex regulates Kit (c-Kit) expression. Conditional deletion of Hhex abolishes transplantation capacity and overcomes radioresistance of Lmo2-transgenic thymocytes. Abrogation of Kit signaling phenocopies Hhex loss in eliminating transplantation capacity and radioresistance, placing Hhex upstream of Kit in the Lmo2-induced self-renewal program. Conditional knockout, bone marrow transplantation, irradiation assay, Kit signaling inhibition Leukemia Medium 25283843
2022 Tel2 promotes hhex transcription by associating with the hhex promoter region during liver regeneration in zebrafish. In tel2 mutants, hhex transcriptional activation in BEC-derived bipotential progenitor cells (BP-PCs) is specifically inhibited, blocking redifferentiation of BP-PCs toward hepatocyte fate. Zebrafish ENU forward genetic screen, tel2 mutant analysis, ChIP at hhex promoter, liver regeneration model Cell reports Medium 35385752
2014 In mouse ES cells, Sox17 is required for Hhex expression and for Cer1 expression. Hhex is required but not sufficient for Cer1 expression downstream of Sox17 in cardiopoiesis. Forced expression of Cer1 rescues cardiac differentiation in Hhex-deficient cells, placing Hhex upstream of Cer1 in the Sox17 pathway for cardiac mesoderm formation. ChIP confirms Sox17-dependent regulation of Cer1 reporter. RNAi, genome-wide profiling, ChIP, luciferase reporter, forced expression rescue Stem cells (Dayton, Ohio) Medium 24585688
1993 HEX was cloned as a novel homeodomain-containing gene expressed in human haematopoietic tissue. The homeodomain is most closely related to HIx and HOX11 proteins. HEX is expressed in multipotential progenitors, B-lymphocyte and myeloid lineages but not in T-lymphocytes or erythroid cells. The human genome contains a single copy gene plus a processed pseudocopy. cDNA cloning, sequence analysis, expression analysis in hematopoietic cells and cell lines Nucleic acids research Medium 8096636

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. Development (Cambridge, England) 432 9389666
2000 The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development (Cambridge, England) 357 10804184
2008 Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes 287 18469204
2004 Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development (Cambridge, England) 203 14736744
2005 Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Developmental biology 199 16364283
2008 Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 188 18633108
2007 Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia 180 17928989
2009 Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proceedings of the National Academy of Sciences of the United States of America 173 20080751
2018 HEx: A heterologous expression platform for the discovery of fungal natural products. Science advances 166 29651464
2005 Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex. Genes & development 158 15687261
2010 Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes 141 20424228
2003 Evaluation of protein docking predictions using Hex 3.1 in CAPRI rounds 1 and 2. Proteins 141 12784374
1993 HEX: a novel homeobox gene expressed during haematopoiesis and conserved between mouse and human. Nucleic acids research 138 8096636
2007 The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Developmental biology 135 17580084
2000 Homeobox gene Hex is essential for onset of mouse embryonic liver development and differentiation of the monocyte lineage. Biochemical and biophysical research communications 134 11027604
2020 The transcription factor Hhex cooperates with the corepressor Tle3 to promote memory B cell development. Nature immunology 124 32601467
2014 The diabetes gene Hhex maintains δ-cell differentiation and islet function. Genes & development 119 24736842
2000 Hhex and scl function in parallel to regulate early endothelial and blood differentiation in zebrafish. Development (Cambridge, England) 107 11003831
2000 Hex-1, a gene unique to filamentous fungi, encodes the major protein of the Woronin body and functions as a plug for septal pores. Fungal genetics and biology : FG & B 103 11273682
2010 Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in type 2 diabetes in a Chinese population. BMC medical genetics 97 20509872
2003 Zebrafish hhex, nk2.1a, and pax2.1 regulate thyroid growth and differentiation downstream of Nodal-dependent transcription factors. Developmental biology 89 14568547
2000 Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function. Development (Cambridge, England) 89 10804173
2010 Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Molecular therapy : the journal of the American Society of Gene Therapy 88 21102561
2001 Distinct enhancer elements control Hex expression during gastrulation and early organogenesis. Developmental biology 86 11397001
2004 A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels. Development (Cambridge, England) 84 15459110
2000 Hex expression suggests a role in the development and function of organs derived from foregut endoderm. Developmental dynamics : an official publication of the American Association of Anatomists 74 10974674
2003 The homeoprotein Hex is required for hemangioblast differentiation. Blood 72 12791650
1999 cDNA cloning and expression of rat homeobox gene, Hex, and functional characterization of the protein. The Biochemical journal 72 10085234
2018 HHEX is a transcriptional regulator of the VEGFC/FLT4/PROX1 signaling axis during vascular development. Nature communications 67 30006544
2003 A HEX-1 crystal lattice required for Woronin body function in Neurospora crassa. Nature structural biology 66 12640443
1999 Expression of the homebox gene Hex during early stages of chick embryo development. Mechanisms of development 65 10096068
2008 Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia. Blood 64 18388181
1997 Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene. Human mutation 61 9090523
2011 A gene regulatory network controlling hhex transcription in the anterior endoderm of the organizer. Developmental biology 60 21215263
2000 Expression and function of the homeodomain-containing protein Hex in thyroid cells. Nucleic acids research 60 10871399
2008 PRH/Hex: an oligomeric transcription factor and multifunctional regulator of cell fate. The Biochemical journal 57 18498250
2005 The homeobox gene HEX regulates proliferation and differentiation of hemangioblasts and endothelial cells during ES cell differentiation. Blood 57 15728128
2008 Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 56 18597214
2000 HNF3beta and GATA-4 transactivate the liver-enriched homeobox gene, Hex. Gene 55 10767553
1999 Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell leukemia. Oncogene 53 10597256
2007 Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population. The Journal of clinical endocrinology and metabolism 52 17971426
1998 Expression of Hex mRNA in early murine postimplantation embryo development. FEBS letters 47 9599004
2018 68Ga-DOTA-GGNle-CycMSHhex targets the melanocortin-1 receptor for melanoma imaging. Science translational medicine 43 30404861
2004 Interaction between hex and GATA transcription factors in vascular endothelial cells inhibits flk-1/KDR-mediated vascular endothelial growth factor signaling. The Journal of biological chemistry 43 15016828
2022 CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis. Nature communications 42 36008411
2008 A honeybee storage protein gene, hex 70a, expressed in developing gonads and nutritionally regulated in adult fat body. Journal of insect physiology 42 18472106
2003 The homeobox gene Hex induces T-cell-derived lymphomas when overexpressed in hematopoietic precursor cells. Oncogene 42 14555989
2006 Hex acts with beta-catenin to regulate anteroposterior patterning via a Groucho-related co-repressor and Nodal. Development (Cambridge, England) 41 16936074
2006 Characterization and expression of the Hex 110 gene encoding a glutamine-rich hexamerin in the honey bee, Apis mellifera. Archives of insect biochemistry and physiology 41 16983665
2016 HHEX: A Crosstalker between HCMV Infection and Proliferation of VSMCs. Frontiers in cellular and infection microbiology 40 27965937
2000 Divergent homeobox gene hex regulates promoter of the Na(+)-dependent bile acid cotransporter. American journal of physiology. Gastrointestinal and liver physiology 40 10915644
2014 A crucial role for the homeodomain transcription factor Hhex in lymphopoiesis. Blood 39 25472970
2003 Impaired B cell development and function in mice with a targeted disruption of the homeobox gene Hex. Proceedings of the National Academy of Sciences of the United States of America 39 12522149
2011 Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway. Oncogene 38 21785462
2022 CRISPR screening uncovers a central requirement for HHEX in pancreatic lineage commitment and plasticity restriction. Nature cell biology 36 35787684
2010 The homeobox gene Hhex regulates the earliest stages of definitive hematopoiesis. Blood 36 20472829
2003 HEX acts as a negative regulator of angiogenesis by modulating the expression of angiogenesis-related gene in endothelial cells in vitro. Arteriosclerosis, thrombosis, and vascular biology 36 12588764
2011 A honey bee hexamerin, HEX 70a, is likely to play an intranuclear role in developing and mature ovarioles and testioles. PloS one 35 22205988
2002 Expression and localization of the homeodomain-containing protein HEX in human thyroid tumors. The Journal of clinical endocrinology and metabolism 35 11889211
2019 Homeobox protein Hhex negatively regulates Treg cells by inhibiting Foxp3 expression and function. Proceedings of the National Academy of Sciences of the United States of America 34 31792183
2015 Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation. Stem cells (Dayton, Ohio) 33 25968920
2010 PRH/Hhex controls cell survival through coordinate transcriptional regulation of vascular endothelial growth factor signaling. Molecular and cellular biology 33 20176809
2006 HEX expression and localization in normal mammary gland and breast carcinoma. BMC cancer 33 16854221
2003 Thyroid-specific transcription factors control Hex promoter activity. Nucleic acids research 32 12655000
2001 Studies of the chemical selectivity of hapten, reactivity, and skin sensitization potency. 1. Synthesis and studies on the reactivity toward model nucleophiles of the (13)C-labeled skin sensitizers hex-1-ene- and hexane-1,3-sultones. Chemical research in toxicology 32 11170514
2019 Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de-repression of cdx1b and pdx1. Journal of molecular cell biology 31 30428031
2012 Polycystic ovary syndrome is not associated with polymorphisms of the TCF7L2, CDKAL1, HHEX, KCNJ11, FTO and SLC30A8 genes. Clinical endocrinology 31 22443257
2010 The homeobox gene Hex regulates hepatocyte differentiation from embryonic stem cell-derived endoderm. Hepatology (Baltimore, Md.) 31 20063280
2004 pha-2 encodes the C. elegans ortholog of the homeodomain protein HEX and is required for the formation of the pharyngeal isthmus. Developmental biology 31 15282157
2013 Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex. The American journal of pathology 30 23665349
2012 Genetic variants of IDE-KIF11-HHEX at 10q23.33 associated with type 2 diabetes risk: a fine-mapping study in Chinese population. PloS one 30 22506066
2009 Interaction between Hhex and SOX13 modulates Wnt/TCF activity. The Journal of biological chemistry 28 20028982
2021 Liver development is restored by blastocyst complementation of HHEX knockout in mice and pigs. Stem cell research & therapy 27 34011403
2018 Impact of KCNQ1, CDKN2A/2B, CDKAL1, HHEX, MTNR1B, SLC30A8, TCF7L2, and UBE2E2 on risk of developing type 2 diabetes in Thai population. BMC medical genetics 27 29871606
2011 Association of genetic variations in TCF7L2, SLC30A8, HHEX, LOC387761, and EXT2 with Type 2 diabetes mellitus in Tunisia. Genetic testing and molecular biomarkers 27 21510814
2018 Alcohol Intake Interacts with CDKAL1, HHEX, and OAS3 Genetic Variants, Associated with the Risk of Type 2 Diabetes by Lowering Insulin Secretion in Korean Adults. Alcoholism, clinical and experimental research 26 30207601
2016 Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a. Genes & development 26 26728554
2016 Misregulation of the proline rich homeodomain (PRH/HHEX) protein in cancer cells and its consequences for tumour growth and invasion. Cell & bioscience 26 26877867
2010 Meta-analysis of the effect of HHEX gene polymorphism on the risk of type 2 diabetes. Mutagenesis 26 21059810
2009 The influence of genetic variations in HHEX gene on insulin metabolism in the German MESYBEPO cohort. Diabetes/metabolism research and reviews 26 19117022
1991 9-(5',6'-dideoxy-beta-D-ribo-hex-5'-ynofuranosyl)adenine, a novel irreversible inhibitor of S-adenosylhomocysteine hydrolase. Biochemistry 26 1911790
2020 Blood platelets stimulate cancer extravasation through TGFβ-mediated downregulation of PRH/HHEX. Oncogenesis 25 32019914
2014 Hhex and Cer1 mediate the Sox17 pathway for cardiac mesoderm formation in embryonic stem cells. Stem cells (Dayton, Ohio) 25 24585688
2012 Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de-repress VEGF-signalling genes and promote cell survival. Nucleic acids research 25 22844093
2011 Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender. European journal of human genetics : EJHG 25 21368910
2008 HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort. European journal of human genetics : EJHG 25 18231124
2002 Down-regulation of the myeloid homeobox protein Hex is essential for normal T-cell development. Immunology 25 12460189
2014 Growth-promoting and tumourigenic activity of c-Myc is suppressed by Hhex. Oncogene 24 25220416
2013 PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin. Oncogene 24 24240683
2009 Polymorphisms of TCF7L2 and HHEX genes in Chinese women with polycystic ovary syndrome. Journal of assisted reproduction and genetics 24 20041287
2009 The PRH/Hex repressor protein causes nuclear retention of Groucho/TLE co-repressors. The Biochemical journal 23 18713067
2025 Microglia-neuron crosstalk through Hex-GM2-MGL2 maintains brain homeostasis. Nature 22 40769205
2006 Hhex is a direct repressor of endothelial cell-specific molecule 1 (ESM-1). Biochemical and biophysical research communications 21 16764824
2004 Functional interaction among thyroid-specific transcription factors: Pax8 regulates the activity of Hex promoter. Molecular and cellular endocrinology 21 15062550
2014 HHEX promotes hepatic-lineage specification through the negative regulation of eomesodermin. PloS one 20 24651531
2011 A potential role for the homeoprotein Hhex in hepatocellular carcinoma progression. Medical oncology (Northwood, London, England) 20 21656028
2004 Effects of Huangqi (Hex) on inducing cell differentiation and cell death in K562 and HEL cells. Acta biochimica et biophysica Sinica 20 15202506
2002 Expression of Hex homeobox gene during skin development: Increase in epidermal cell proliferation by transfecting the Hex to the dermis. Development, growth & differentiation 20 12175363
2022 Tel2 regulates redifferentiation of bipotential progenitor cells via Hhex during zebrafish liver regeneration. Cell reports 19 35385752
2014 Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice. Leukemia 19 25283843

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