Affinage

HAND2

Heart- and neural crest derivatives-expressed protein 2 · UniProt P61296

Length
217 aa
Mass
23.7 kDa
Annotated
2026-06-10
100 papers in source corpus 55 papers cited in narrative 55 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

HAND2 is a basic helix-loop-helix transcription factor that orchestrates morphogenesis across multiple mesodermal and neural crest-derived lineages, most prominently as an essential determinant of right ventricular formation and cardiac neural crest morphogenesis, where its loss is embryonic lethal (PMID:9171826). It acts as a transcriptional activator by binding E-boxes as a heterodimer with E-proteins through its bHLH region (PMID:11812799), but a defining feature is its dual mode of action: a DNA binding-dead knock-in rescues early cardiac and branchial arch defects yet fails to rescue limb growth, showing that limb patterning requires direct DNA binding while early cardiac and craniofacial functions proceed through DNA binding-independent protein-protein interactions (PMID:19211672, PMID:12070084). Through its HLH motif HAND2 dimerizes with E-proteins and HRT/Hairy-related factors (PMID:10924525) and engages partners including MEF2C (PMID:15486975), the homeoprotein Phox2a/Arix together with CBP at the DBH promoter (PMID:14506227, PMID:14512028), and Runx2, whose DNA binding it directly inhibits to restrain osteoblast differentiation in the branchial arch (PMID:19144722). In the limb, HAND2 occupies posterior cis-regulatory modules and binds the ZRS enhancer in complexes with Hoxd13 to activate Shh, in reciprocal antagonism with Gli3 that establishes anterior-posterior polarity (PMID:10804186, PMID:20386744, PMID:11850405, PMID:25453830). In the sympathetic and enteric nervous systems HAND2 acts downstream of BMP/Phox2b as the primary determinant of noradrenergic differentiation, required for TH and DBH expression (PMID:10952904, PMID:17008447, PMID:17531968, PMID:17507395). Its own transcription is controlled by a GATA-dependent right ventricular enhancer (PMID:11076755), an ET-1/Dlx6-dependent branchial arch enhancer (PMID:11711438, PMID:12571099), calcineurin/Nfat signaling with miR-25 and miR-133a (PMID:24161931, PMID:20974915), and a super-enhancer whose activity depends on transcription of the overlapping lncRNA locus Hand2os1/Upperhand (PMID:27783597, PMID:31273086). Beyond development, HAND2 functions as an endometrial tumor suppressor that is silenced by hypermethylation in endometrial cancer and directly activates IL15 in stromal cells (PMID:24265601, PMID:32444497), drives pathological cardiac hypertrophy when re-expressed in adult myocardium (PMID:24161931), and modulates chromatin accessibility to enable MYCN-driven transcription in neuroblastoma (PMID:36598365).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1997 High

    Established HAND2 as an essential, non-redundant transcription factor by showing which structures fail without it, defining its core developmental role.

    Evidence Targeted gene knockout in mice with phenotypic analysis

    PMID:9171826

    Open questions at the time
    • Did not define direct transcriptional targets
    • Did not distinguish autonomous vs non-autonomous functions
  2. 1998 High

    Placed HAND2 within signaling hierarchies and showed it specifies chamber identity rather than left-right position, clarifying what developmental information it encodes.

    Evidence Epistasis in Edn1-null and dHAND-null embryos; expression analysis in inv/inv mutants

    PMID:9576835 PMID:9671575

    Open questions at the time
    • Mechanism of chamber-specific expression unresolved
    • Direct vs indirect regulation of Msx1 not established
  3. 2000 High

    Defined HAND2 as a posteriorly-restricted upstream activator of Shh in the limb ZPA and a regulator of vascular smooth muscle differentiation, extending its roles beyond the heart.

    Evidence Null and transgenic misexpression analysis; subtractive hybridization identifying neuropilin-1

    PMID:10675351 PMID:10804186

    Open questions at the time
    • Direct binding at Shh regulatory elements not yet shown
    • Whether Shh regulation is DNA-binding-dependent unknown at this stage
  4. 2000 High

    Identified the upstream transcriptional control of HAND2 itself, showing GATA factors drive its right ventricular expression through a defined enhancer.

    Evidence Transgenic reporter analysis with enhancer deletion and GATA-site mutation in mice

    PMID:11076755

    Open questions at the time
    • Did not identify which GATA factor binds in vivo
    • Other inputs to RV enhancer not addressed
  5. 2000 High

    Defined HAND2's biochemical dimerization repertoire and DNA-binding mode, providing the molecular basis for its activator function.

    Evidence Yeast/mammalian two-hybrid, pull-down, EMSA, and one-hybrid/reporter assays

    PMID:10924525 PMID:11812799

    Open questions at the time
    • In vivo relevance of homodimers vs HRT heterodimers unclear
    • Target genes of E12 heterodimer not defined
  6. 2000 High

    Positioned HAND2 as a BMP/Phox2b-downstream effector of sympathetic neuron specification, beginning its definition as a noradrenergic determinant.

    Evidence BMP4 overexpression, noggin inhibition, and dHAND misexpression in chick

    PMID:10952904

    Open questions at the time
    • Direct neuronal target genes not identified
    • Mechanism of phenotype specification unresolved
  7. 2001 High

    Built the combinatorial cardiac transcription network around HAND2, showing it cooperates with Nkx2.5 for ventricle formation, and identified Dlx6 and Irx4 as network nodes.

    Evidence Double-null mouse epistasis; enhancer EMSA with EdnrA-mutant extracts

    PMID:10625552 PMID:11711438 PMID:11784028

    Open questions at the time
    • Direct protein-protein contact with Nkx2.5 not demonstrated here
    • Whether Irx4 regulation is direct unresolved
  8. 2002 High

    Revealed that HAND2 can act through its HLH dimerization motif independent of its own DNA binding, splitting its function into DNA-binding-dependent and -independent modes.

    Evidence Domain-deletion transgenic misexpression in mouse limb plus reporter assays; Gli3/dHAND genetic antagonism

    PMID:11850405 PMID:12070084

    Open questions at the time
    • Identity of HLH-mediated partners in limb not defined
    • Direct ZRS binding not yet shown
  9. 2003 High

    Defined HAND2's craniofacial requirement via a dedicated ET-1-dependent enhancer and its DNA-binding-independent potentiation of Phox2a at the DBH promoter through CBP.

    Evidence Enhancer deletion in mice; co-IP, EMSA, promoter mutagenesis, and E1A inhibition in cell lines

    PMID:12571099 PMID:14506227 PMID:14512028

    Open questions at the time
    • Whether CBP recruitment is direct not established
    • In vivo confirmation of DBH mechanism not shown
  10. 2004 High

    Expanded HAND2's interaction network and showed dosage-dependent redundancy with Hand1, and identified MEF2C and JAB1 as functional partners.

    Evidence Conditional/double-mutant mice; GST pulldown, co-IP, ChIP, EMSA; yeast two-hybrid

    PMID:15139020 PMID:15486975 PMID:15576406

    Open questions at the time
    • JAB1 finding rests on single lab without in vivo confirmation
    • Genome-wide MEF2C co-targets not defined
  11. 2005 High

    Showed HAND2 dimer-partner choice is regulated by PKA/PP2A phosphorylation and that it directs myocardial epithelialization, adding post-translational control and a cell-biological role.

    Evidence Transgenic/genetic antagonism with Twist1 and phosphorylation analysis; zebrafish polarity assays vs gata5

    PMID:15735646 PMID:15786591

    Open questions at the time
    • Phosphosite stoichiometry in vivo not quantified
    • Mechanism linking Hand2 to polarity machinery unknown
  12. 2006 High

    Cemented HAND2 as the selective noradrenergic determinant of sympathetic neurons, separable from generic neuronal differentiation, using cross-species loss-of-function.

    Evidence Zebrafish hand2 mutant marker analysis; mouse Wnt1-Cre conditional knockout

    PMID:17008447 PMID:17531968

    Open questions at the time
    • Direct binding at th/dbh regulatory regions not shown here
    • Whether Hand1 dependency is direct unclear
  13. 2007 High

    Extended the noradrenergic role to enteric neurons and linked HAND2's nuclear-to-cytoplasmic relocalization to its differentiation function.

    Evidence Conditional inactivation, explant culture, siRNA, subcellular immunostaining

    PMID:17507395

    Open questions at the time
    • Mechanism controlling nuclear export not identified
    • Functional significance of cytoplasmic Hand2 untested
  14. 2008 High

    Distinguished cell-autonomous from non-autonomous HAND2 functions in cardiac neural crest, showing it controls outflow tract alignment partly via norepinephrine and signaling to second heart field.

    Evidence Neural crest conditional knockout with adrenergic rescue and phenotyping

    PMID:19008477

    Open questions at the time
    • Identity of the second-heart-field signal not defined
    • Direct targets in cNC unresolved
  15. 2009 High

    Formalized the DNA-binding-dependent vs -independent dichotomy in vivo and uncovered repressive mechanisms: direct inhibition of Runx2 DNA binding and dimer-independent chondrogenesis repression.

    Evidence EDE DNA-binding-dead knock-in; co-IP/pulldown with Runx2; micromass and Col2a1-transgenic overexpression; palate-epithelium conditional KO

    PMID:19144722 PMID:19211672 PMID:19341725 PMID:19932774

    Open questions at the time
    • Structural basis of Runx2 inhibition unknown
    • Chondrogenesis repression mechanism (DNA-binding-independent) lacks defined cofactor
  16. 2010 High

    Provided direct chromatin evidence for HAND2 at the ZRS with Hoxd13 and revealed unexpected roles in ECM remodeling and cardiac fusion through fibronectin and MMP regulation.

    Evidence ChIP, co-IP, reporter, Hand2/Gli3 double mutants; zebrafish loss-of-function with MMP/laminin/fn1 assays and rescue

    PMID:20386744 PMID:20573696 PMID:20627079 PMID:20724450 PMID:25038045

    Open questions at the time
    • Direct vs indirect control of fn1/MMP not resolved
    • Whether ZRS binding requires Hand2 DNA contact vs partner-mediated unclear
  17. 2010 High

    Identified miR-133a as a post-transcriptional regulator of HAND2, complementing GATA-, ET-1-, and signaling-based transcriptional control.

    Evidence Affinity purification against Hand2 3'UTR, reporter assay, miR-133a double knockout mice

    PMID:20974915

    Open questions at the time
    • Tissue context of miR-133a regulation not fully mapped
    • Interplay with other Hand2-targeting miRNAs unaddressed
  18. 2011 High

    Defined a Dlx5/6-Hand2-Runx2 negative feedback loop in the branchial arch and a Hand1-to-Hand2 hierarchy in epicardial progenitors, sharpening craniofacial and coronary development models.

    Evidence Conditional knockouts with molecular marker and phenotypic analysis

    PMID:21350214 PMID:21558373

    Open questions at the time
    • Direct binding at Dlx5/6 loci not demonstrated
    • Mechanism of ECM/Pdgfr dysregulation in epicardium unclear
  19. 2012 High

    Demonstrated direct HAND2 occupancy with Phox2b at a sympathetic Hand1 cis-element and placed Isl1 upstream of the hindlimb Hand2-Shh pathway.

    Evidence Transgenic reporter, ChIP, EMSA, mutational analysis; hindlimb conditional Isl1 knockout

    PMID:22323723 PMID:22438573

    Open questions at the time
    • Forelimb vs hindlimb Hand2 input difference unexplained
    • Genome-wide sympathetic targets not yet mapped
  20. 2013 High

    Identified HAND2 as an endometrial tumor suppressor silenced by hypermethylation and as a calcineurin/Nfat-miR-25 effector whose adult re-expression drives pathological hypertrophy, expanding its disease relevance.

    Evidence Methylation analysis with endometrial conditional KO; bidirectional cardiac genetic manipulation with antagomir and pressure overload

    PMID:24161931 PMID:24265601

    Open questions at the time
    • Direct HAND2 targets driving hypertrophy not fully defined
    • Link between PTEN loss and HAND2 silencing mechanistically incomplete
  21. 2014 High

    Mapped HAND2 chromatin occupancy genome-wide, identifying target regulatory networks (Gli3, Tbx3) for limb polarity and Neuregulin1/Snai1 for cardiac valve and EMT programs.

    Evidence ChIP-seq from embryos/limb buds and hearts with transcriptomics, conditional KO, and explant rescue

    PMID:25453830 PMID:25497097 PMID:28538179

    Open questions at the time
    • Direct vs cofactor-mediated occupancy at many CRMs unresolved
    • Tissue-specific cofactor determinants of binding not defined
  22. 2015 Medium

    Linked specific human HAND2 missense mutations to congenital heart disease by showing they impair transcriptional activity and synergy with GATA4/NKX2.5.

    Evidence Patient sequencing with dual-luciferase reporter assays for L47P and S65I

    PMID:26676105 PMID:26865696

    Open questions at the time
    • Functional assays limited to reporters in cell lines
    • Causality not established by animal models or family segregation alone
  23. 2016 High

    Revealed that transcription through the Hand2os1/Upperhand locus, rather than the mature lncRNA, maintains the Hand2 super-enhancer and is required for Hand2 expression and right ventricular development.

    Evidence Promoter-deletion knock-in mice with H3K27ac and Pol II ChIP, transcript knockdown vs transcription blockade

    PMID:27783597

    Open questions at the time
    • Whether transcription acts purely in cis not fully resolved
    • Mechanism coupling Pol II elongation to enhancer activity incomplete
  24. 2019 High

    Showed HAND2 reorganizes chromatin accessibility to drive cell-fate reprogramming and that the Hand2os1 locus quantitatively dampens HAND2 to restrain cardiomyocyte proliferation, defining HAND2 as a chromatin and dosage-sensitive regulator.

    Evidence ATAC-seq/RNA-seq with N-terminal domain analysis in reprogramming; full-length vs promoter-deletion lncRNA knockouts with single-cell RNA-seq

    PMID:31116981 PMID:31273086

    Open questions at the time
    • Pioneer-like activity mechanism not biochemically defined
    • How locus dosage is sensed by Hand2 promoter unclear
  25. 2020 High

    Established that HAND2 directly activates IL15 in human endometrial stroma and synergizes with Gli3 at low-affinity divergent Gli motifs for mandibular development, defining context-specific direct target genes.

    Evidence ChIP-qPCR and reporter mutagenesis in human ESCs; Gli3/Hand2 ChIP-seq co-occupancy and reporter assays in mouse

    PMID:32444497 PMID:33006313

    Open questions at the time
    • Cofactor requirements for IL15 activation not defined
    • Generality of dGBM mechanism to other tissues untested
  26. 2022 Medium

    Defined HAND2 as a marker and regulator of mesothelial progenitors in lateral plate mesoderm, broadening its known progenitor-specifying roles, and linked it to gestational regulation in endometrium.

    Evidence Zebrafish loss-of-function with single-cell RNA-seq and live imaging; evolutionary transcriptomics and chromatin looping in endometrium

    PMID:33522483 PMID:35354817

    Open questions at the time
    • Estrogen-suppression claim rests largely on comparative analysis
    • Direct mesothelial target genes not identified
  27. 2023 High

    Showed HAND2 cooperates with MYCN to compete with nucleosomes and open enhancers in neuroblastoma, defining a targetable oncogenic chromatin mechanism.

    Evidence ChIP-seq, ATAC-seq, co-occupancy analysis, and Aurora A/HDAC inhibitor combination in neuroblastoma models

    PMID:36598365

    Open questions at the time
    • Direct HAND2-MYCN physical interaction not biochemically resolved
    • Whether dependency generalizes beyond MYCN-amplified neuroblastoma unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HAND2 selects among its many partners and switches between DNA-binding-dependent activation and DNA-binding-independent protein-protein mechanisms in a tissue-specific manner remains unresolved.
  • No structure of HAND2 in complex with partners or DNA
  • Tissue-specific determinants of dual-mode switching not defined
  • Mechanism coupling phosphorylation, partner choice, and target selection incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3
Partners
GLI3HOXD13JAB1MEF2CMYCNPHOX2ARUNX2TCF3

Evidence

Reading pass · 55 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Targeted gene deletion of dHAND (HAND2) in mice results in embryonic lethality at E10.5 due to failure to form the mesodermally derived right ventricle and neural crest-derived aortic arches, establishing HAND2 as an essential transcription factor for right ventricular development and cardiac neural crest morphogenesis. Targeted gene knockout in mice with phenotypic analysis Nature genetics High 9171826
1998 dHAND is expressed in branchial arch mesenchyme downstream of endothelin-1 (ET-1) epithelial signaling; in Edn1-null embryos dHAND is downregulated, and in dHAND-null embryos the homeobox gene Msx1 is absent from branchial arch mesenchyme but not limb bud, placing dHAND in a signaling cascade: ET-1 → dHAND → Msx1 in branchial arch development. Epistasis analysis using Edn1-null and dHAND-null mouse embryos with molecular marker expression analysis Development (Cambridge, England) High 9671575
1998 dHAND and eHAND are expressed in the pulmonary (right) and systemic (left) ventricles respectively, independent of left-right sidedness; in situs inversus (inv/inv) mice, the chamber-type specificity of HAND expression is maintained even when anatomic position is reversed, demonstrating HAND genes specify chamber identity rather than left-right looping direction. Expression analysis in inv/inv mutant mouse embryos with cardiac phenotyping Developmental biology High 9576835
2000 dHAND is expressed posteriorly in the developing limb prior to Shh and is required for Shh expression in the zone of polarizing activity (ZPA); dHAND-null embryos lack Shh expression and have severely underdeveloped limb buds, while anterior misexpression of dHAND in transgenic mice causes ectopic ZPA formation, ectopic Shh expression, and preaxial polydactyly. Additionally, Hedgehog signaling maintains dHAND expression in a feedback loop. Null allele analysis, transgenic misexpression, and molecular marker analysis in mouse embryos Development (Cambridge, England) High 10804186
2000 dHAND is required for vascular development; targeted deletion reveals defects in vascular mesenchymal cell differentiation into vascular smooth muscle cells (VSMCs) and failure of these cells to contact endothelial cells. Subtractive hybridization identified neuropilin-1 (VEGF165 receptor) as a dHAND-dependent gene downregulated in dHAND-null hearts. Targeted gene knockout in mice, subtractive hybridization, phenotypic analysis The Journal of clinical investigation High 10675351
2000 A GATA-dependent right ventricular enhancer controls dHAND transcription; mutation of two conserved GATA consensus sites within a 1.5 kb cardiac enhancer abolishes transgene expression in the right ventricle, identifying dHAND as a direct transcriptional target of GATA factors during right ventricle development. Transgenic reporter gene analysis with deletion and site-specific mutation of enhancer elements in mice Development (Cambridge, England) High 11076755
2000 dHAND and eHAND can form homo- and heterodimers with each other and with Hairy-related transcription factors HRT1-3, demonstrated by yeast two-hybrid, mammalian two-hybrid, and biochemical pull-down assays. dHAND and eHAND can negatively regulate DNA binding of MyoD/E12 heterodimers in competition gel shift assays. Yeast two-hybrid, mammalian two-hybrid, biochemical pull-down, competition gel shift (EMSA) The Journal of biological chemistry High 10924525
2000 dHAND is a downstream transcriptional effector of BMP signaling in sympathetic neuron specification; BMP4 overexpression induces dHAND expression in vivo and in vitro, noggin-mediated BMP inhibition blocks dHAND expression, and dHAND misexpression generates ectopic sympathetic neurons in vivo. dHAND acts downstream of Phox2b in the BMP-induced sympathetic differentiation cascade. BMP4 overexpression, noggin-mediated BMP inhibition in vivo/in vitro, dHAND misexpression in chick embryos Development (Cambridge, England) High 10952904
2000 Irx4 expression in the ventricular myocardium is downstream of Nkx2-5 and dHAND; Nkx2-5-null embryos have markedly reduced Irx4 transcript levels, and dHAND-null embryos initiate but cannot maintain normal Irx4 expression. Expression analysis in Nkx2-5 and dHAND null mouse embryos Developmental biology Medium 10625552
2001 A conserved dHAND branchial arch enhancer requires ET-1 signaling for activity and contains four homeodomain binding sites required for expression; Dlx6 was identified as an ET-1-dependent factor that binds these sites in branchial arch extracts and is downregulated in EdnrA-null mice, establishing Dlx6 as an intermediary between ET-1 signaling and dHAND transcription. Transgenic reporter gene analysis, EMSA with nuclear extracts from EdnrA mutant vs. wild-type embryos, enhancer deletion analysis Genes & development High 11711438
2001 Nkx2.5 and dHAND function combinatorially for cardiac ventricle formation; Nkx2.5(-/-)dHAND(-/-) double mutants show complete ventricular dysgenesis (only atrial chamber), while single mutants retain one ventricular chamber. Nkx2.5 is required for eHAND expression in precardiac mesoderm, and both Nkx2.5 and dHAND cooperatively regulate Irx4 expression. Genetic epistasis using double-null mouse mutants with molecular marker analysis Developmental biology High 11784028
2002 GLI3 restricts dHAND expression to posterior limb mesenchyme prior to SHH signaling, while dHAND in turn excludes anterior genes (Gli3, Alx4) from posterior mesenchyme. Genetic interaction of GLI3 and dHAND directs BMP antagonist GREMLIN posteriorly to establish the SHH/FGF feedback loop. Genetic epistasis analysis in Gli3 and dHAND mouse mutants with molecular marker expression Genes & development High 11850405
2002 HAND2 functions as a transcriptional activator by binding E-boxes as a heterodimer with E-proteins (E12); HAND2 contains a strong N-terminal transcriptional activation domain (mammalian one-hybrid), the consensus DNA binding site was determined, and yeast two-hybrid screening confirmed HAND2 homodimerization in vitro but not in mammalian two-hybrid, with robust HAND2/E12 heterodimer interaction. Mammalian one-hybrid, yeast two-hybrid, EMSA, reporter gene assays The Journal of biological chemistry High 11812799
2002 dHAND induces ectopic digits and Shh expression in the anterior limb bud through its HLH dimerization motif alone, independent of the transcriptional activation domain and basic DNA-binding region. An N-terminal transcriptional activation domain and bHLH region are required for E-box-dependent transcription in vitro, but digit duplication in vivo requires only the HLH motif, suggesting dHAND acts via protein-protein interactions independent of direct DNA binding in this context. Structure-function analysis with domain deletion mutants, transgenic misexpression in mouse limb buds, reporter gene assays in cultured cells Development (Cambridge, England) High 12070084
2003 dHAND in the branchial arches is required for craniofacial development; targeted deletion of the ET-1-dependent branchial arch enhancer abolishes dHAND expression in ventrolateral first and second branchial arches but preserves expression in a ventral domain where eHAND is co-expressed, causing cleft palate, mandibular hypoplasia, and cartilage malformations. Targeted enhancer deletion by homologous recombination, phenotypic and expression analysis Development (Cambridge, England) High 12571099
2003 dHAND (HAND2) at the DBH promoter potentiates Arix/Phox2a transcriptional activity through direct protein-protein interaction (co-precipitation demonstrated); dHAND enhancement of Arix-driven DBH transcription is independent of dHAND direct DNA binding (a basic domain mutant shows equal or greater potentiation), and is blocked by E1A, implicating CBP in the complex. Co-immunoprecipitation, EMSA, transient transfection with luciferase reporters, E1A inhibition The Journal of biological chemistry High 14506227
2003 HAND2 synergistically enhances Phox2a-driven transcription at the DBH promoter; HAND2 activates DBH without directly binding E-boxes, requiring the CRE/AP1-HD1/2 domains for synergistic activity, and does not functionally dimerize with E12 in this transcriptional complex. The interaction with CBP (blocked by E1A) is required. Transient transfection with luciferase reporters, promoter mutagenesis, E1A inhibition in P19/NT-2 cells Developmental biology High 14512028
2004 Hand1 and Hand2 have gene dosage-dependent, partially redundant roles in cardiac morphogenesis; conditional cardiac Hand1 deletion causes left ventricular defects, and Hand1/2 double mutants reveal synergistic requirements for both factors in ventricular gene expression and cardiomyocyte differentiation. Conditional knockout using cardiac Cre, Hand1/2 double mutant analysis, gene expression profiling Development (Cambridge, England) High 15576406
2004 dHAND and MEF2C physically interact (GST pulldown and co-immunoprecipitation) and synergistically activate the ANP promoter in transfected HeLa cells without affecting each other's DNA binding activity; ChIP in H9c2 cells confirms that dHAND interacts with MEF2C in a protein complex that binds the A/T sequence in the ANP promoter. GST pulldown, co-immunoprecipitation, EMSA, chromatin immunoprecipitation (ChIP), reporter gene assay Journal of cellular biochemistry High 15486975
2004 JAB1 binds directly to the HLH domain of HAND2 (yeast two-hybrid, confirmed biochemically) and enhances HAND2 transcriptional activity by increasing HAND2 DNA binding, an effect mediated through the HLH domain rather than the basic DNA-binding domain. Yeast two-hybrid screen, biochemical binding assays, reporter gene assay, EMSA Journal of neuroscience research Medium 15139020
2005 Twist1 and Hand2 dimerization partner choice is modulated by protein kinase A (PKA)- and protein phosphatase 2A (PP2A)-regulated phosphorylation of conserved helix I residues; ectopic Hand2 expression phenocopies Twist1 loss of function in the limb, and the two factors have gene dosage-dependent antagonistic interaction. Multiple Saethre-Chotzen Twist1 mutations alter PKA-mediated phosphorylation. Transgenic misexpression, genetic epistasis in mice, phosphorylation analysis with PKA/PP2A modulators, dimerization assays Nature genetics High 15735646
2005 Hand2 is required for myocardial cell polarization (epithelial formation) during myocardial differentiation in zebrafish; hand2 mutants have myocardial precursors that fail to polarize, while gata5 mutants with a similar reduction in myocardial cell number retain polarized epithelia, demonstrating Hand2 specifically regulates myocardial epithelialization. Zebrafish mutant analysis, cell polarity assays, comparison of hand2 and gata5 mutants Current biology : CB High 15786591
2006 In zebrafish hands off (hand2 deletion) mutants, sympathetic precursors form normal ganglion primordia expressing phox2b, phox2a, and ascl1, but expression of noradrenergic markers th and dbh is strongly reduced, as well as gata2 and tfap2a; generic neuronal differentiation (elavl3/HuC) is unaffected, demonstrating Hand2 is selectively required for noradrenergic differentiation of sympathetic neurons. Zebrafish hand2 deletion mutant analysis with molecular marker expression (ISH/IHC) Development (Cambridge, England) High 17008447
2007 Conditional Hand2 knockout in Wnt1-Cre neural crest-derived cells demonstrates that Hand2 is the primary determinant of noradrenergic (catecholaminergic) phenotype in the sympathetic nervous system; TH and DBH are dramatically reduced in mutants, while pan-neuronal markers and other SNS transcription factors (Phox2a/b, Mash1, Gata2/3) are unaffected. Hand2 is required for Hand1 expression in this lineage. Conditional knockout (Wnt1-Cre x floxed Hand2), immunohistochemistry, gene expression analysis Developmental biology High 17531968
2007 Hand2 is required for terminal differentiation of enteric neurons from neural crest-derived precursors but not for their migration into the gut or for glia formation; Hand2 is intranuclear in enteric precursors but cytoplasmic in differentiated neurons. siRNA silencing of Hand2 prevents neuronal development in explants. Conditional Hand2 inactivation in migrating neural crest cells, organ explant cultures, siRNA knockdown, subcellular localization by immunostaining Development (Cambridge, England) High 17507395
2008 Cardiac neural crest (cNC) Hand2 expression is required for proper outflow tract alignment and aortic arch artery development; loss of Hand2 in the neural crest lineage (rescued by restoring norepinephrine synthesis) causes outflow tract misalignment, pulmonary stenosis, interrupted aortic arch, retroesophageal right subclavian artery, and VSD without affecting cNC migration or survival. Hand2 in cNC regulates signaling to second heart field myocardium. Conditional knockout in neural crest (rescued from early lethality by adrenergic receptor activation), phenotypic analysis, molecular marker analysis Circulation research High 19008477
2009 Hand2 controls osteoblast differentiation in branchial arch by directly inhibiting Runx2 DNA binding; Hand proteins physically interact with Runx2 via the Hand N-terminal domain (co-IP, pulldown), suppressing Runx2 DNA binding and transcriptional activity in a manner independent of Hand dimerization with bHLH partners or Hand's own DNA binding. Hand2 hypomorphic mice show accelerated osteoblast differentiation and ectopic bone in the mandible with upregulated/ectopic Runx2. Co-immunoprecipitation, GST pulldown, reporter gene assay, domain deletion analysis, Hand2 hypomorphic mouse analysis Development (Cambridge, England) High 19144722
2009 Hand2 is required in the palate epithelium (not mesenchyme) for palatogenesis; epithelial-specific Hand2 deletion causes cleft palate with premature periderm cell death, downregulation of Shh in the medial edge epithelium, and decreased mesenchymal cell proliferation. BMP signaling is required for Hand2 expression in the palate epithelium. Tissue-specific conditional knockout (epithelial vs. mesenchymal Cre lines), phenotypic analysis, molecular marker expression Developmental biology High 19341725
2009 Hand2 represses chondrogenesis in a DNA binding- and dimer formation-independent manner; overexpression in micromass cultures suppresses chondrogenic genes (Sox9, Col2a1, aggrecan). Hand2 is induced by canonical Wnt signaling. Transgenic overexpression targeted to cartilage causes dwarfism with skeletal deformities by inhibiting endochondral ossification and slowing chondrocyte maturation. Limb bud micromass culture overexpression, domain mutant analysis, Col2a1-driven transgenic overexpression in mice Bone Medium 19932774
2009 Hand2 can regulate gene expression through DNA binding-dependent and DNA binding-independent mechanisms in vivo; a Hand2 EDE mutation abolishing DNA binding rescues early cardiac and branchial arch defects seen in null embryos but does not rescue limb bud growth defects, demonstrating that limb functions require DNA binding while cardiac and branchial arch early functions do not. Knock-in mouse with EDE DNA-binding-dead mutation, comparison to null phenotype Development (Cambridge, England) High 19211672
2010 HAND2 in limb buds is part of chromatin complexes containing Hoxd13; ChIP shows Hand2-containing complexes bind the ZRS far-upstream cis-regulatory region required for Shh expression in limb buds. Hand2 and Hoxd13 transactivate gene expression via the ZRS, while Gli3 repressor isoform interferes with this. Loss of both Hand2 and Gli3 causes complete loss of AP polarity and extreme polydactyly. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, reporter gene assay, genetic epistasis (Hand2/Gli3 double mutant mice) PLoS genetics High 20386744
2010 In zebrafish, Hand2 loss reduces matrix metalloproteinase (MMP) activity and prolongs laminin deposition at the lateral plate mesoderm (LPM)/gut boundary, preventing asymmetric LPM migration and gut looping; hand2-expressing cells normally diminish laminin in an MMP-dependent manner, revealing an unexpected role for Hand2 in ECM remodeling during organogenesis. Zebrafish genetic loss-of-function, transgenic EGFP reporter live imaging, MMP activity assays, laminin immunostaining Developmental cell High 20627079
2010 Hand2 negatively regulates fibronectin 1 (fn1) levels to create a permissive environment for cardiac fusion; hand2 mutant zebrafish embryos show elevated fn1 expression, hand2 overexpression decreases Fibronectin, and reducing fn1 function rescues cardiac fusion defects in hand2 mutants, demonstrating a non-autonomous role for Hand2 in cardiomyocyte movement. Zebrafish genetic loss-of-function, mosaic analysis, gene expression profiling, fn1 loss-of-function rescue experiment Development (Cambridge, England) High 20724450
2010 Hand2 specifies ventral identity in zebrafish pharyngeal arches in part by repressing dlx3b/4b/5a expression; hand2 mutants show expanded bapx1 and dlx3b/4b/5a expression domains. Hand2 and Dlx genes delineate dorsal, intermediate and ventral domain boundaries within pharyngeal arches, with hand2 repressing intermediate (joint region) and dorsal fates. Morpholino knockdown in zebrafish, mutant analysis, in situ hybridization for domain markers Development (Cambridge, England) High 20573696
2010 Hand2 elevates cardiomyocyte production in zebrafish through interactions in multimeric complexes independent of direct DNA binding; overexpression enhances cardiomyocyte production by promoting division of late-differentiating second heart field cardiac progenitors and by altering anterior lateral plate mesoderm patterning. Zebrafish overexpression, proliferation assays, comparison of DNA-binding mutants Development (Cambridge, England) Medium 25038045
2010 miR-133a, identified by affinity purification against the Hand2 3'UTR, inhibits Hand2 expression in tissue culture; miR-133a double knockout mice have elevated Hand2 mRNA and protein, establishing Hand2 as a target of miR-133a regulation in addition to miR-1. Affinity purification of miRNAs with Hand2 3'UTR, sequential binding assay, reporter assay, miR-133a double knockout mouse analysis Proceedings of the National Academy of Sciences of the United States of America High 20974915
2011 Hand2 in the branchial arch ectomesenchyme establishes a negative feedback loop by repressing Dlx5 and Dlx6 expression in the distal arch following Dlx5/Dlx6-mediated induction of Hand2; failure to repress Dlx5/Dlx6 causes upregulation of Runx2, ectopic bone formation, proximal-distal duplication, and aglossia. Conditional Hand2 knockout, molecular marker expression analysis, phenotypic characterization in mice Development (Cambridge, England) High 21558373
2011 Hand2 loss-of-function in Hand1-expressing epicardial progenitors causes defective epicardialization and failure to form coronary arteries, coincident with altered ECM deposition and Pdgfr expression, demonstrating hierarchal relationship: transient Hand1 expression in septum transversum defines epicardial precursors that subsequently depend on Hand2. Hand1-Cre conditional deletion of Hand2, phenotypic and molecular analysis Circulation research High 21350214
2012 A Hand1 cis-regulatory element (1007 bp) is sufficient to drive sympathetic chain reporter expression and is directly bound by Hand2 and Phox2b as confirmed by ChIP and EMSA; mutational analysis shows conserved Phox2 and E-box sites are necessary for activity; Hand2 is required for reporter activation in a gene dosage-dependent manner; Hand2 and Hand1 bind E-boxes within this element differentially. Transgenic reporter analysis, ChIP, EMSA, mutational analysis, conditional and hypomorphic Hand2 mouse models The Journal of neuroscience : the official journal of the Society for Neuroscience High 22323723
2012 Islet1 (Isl1) functions upstream of the Hand2-Shh pathway specifically in the hindlimb field; conditional Isl1 inactivation in the hindlimb-forming region downregulates Hand2 expression and severely impairs Shh expression in the hindlimb bud but not the forelimb bud. Conditional knockout (Hoxb6Cre), expression analysis in forelimb vs. hindlimb Development (Cambridge, England) High 22438573
2013 HAND2 is a hub of endometrial epigenetic regulation; HAND2 is one of the most commonly hypermethylated and silenced genes in endometrial cancer. Mice with endometrium-specific Hand2 knockout develop precancerous endometrial lesions with lack of PTEN expression, demonstrating a functional tumor suppressor role for HAND2 in endometrial stroma. Epigenome-wide methylation analysis, conditional endometrial Hand2 knockout mouse, histopathology, PTEN expression analysis PLoS medicine High 24265601
2013 Nfat (calcineurin/Nfat signaling) and decreased miR-25 expression cooperate to re-express Hand2 in the diseased myocardium; Hand2 overexpression in healthy cardiomyocytes causes pathological hypertrophy, while conditional Hand2 knockout confers marked resistance to pressure-overload-induced hypertrophy, fibrosis, and ventricular dysfunction. In vivo miR-25 inhibition evokes cardiac dysfunction in a Hand2-dependent manner. Conditional overexpression and knockout mouse models, antagomir in vivo administration, pressure overload model Nature cell biology High 24161931
2014 Genome-wide HAND2 chromatin complex mapping (ChIP-seq) from mouse embryos and limb buds identifies HAND2 target cis-regulatory modules (CRMs) controlling expression of transcriptional regulators (including Gli3 and Tbx3) that establish anterior-posterior polarity; TBX3 acts downstream of HAND2 to refine posterior Gli3 expression boundary. ChIP-seq from mouse embryos and limb buds, transgenic reporter assays, conditional knockout Developmental cell High 25453830
2014 Endocardial Hand2 is an essential downstream effector of Notch signaling in the endocardium; endocardial Hand2 ablation causes failure to develop a patent tricuspid valve, VSD, and hypotrabeculation. Hand2 directly regulates Neuregulin1 transcription and is required for proper endocardium-to-myocardium signaling. Hand2 mutant hearts also show dysregulation of Vegf signaling components (VegfA, VegfR2, Nrp1, VegfR3). Endocardium-specific conditional Hand2 knockout, ChIP, reporter gene assays, molecular marker expression analysis Cell reports High 25497097
2014 Combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and Hand2-deficient AVC tissue identifies HAND2 target gene regulatory networks governing EMT during atrioventricular canal cardiac cushion formation; Snai1 (EMT master regulator) is lost from Hand2-deficient AVCs and re-expression of Snai1 partially restores EMT in mutant AVC explants; HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts. ChIP-seq, transcriptome analysis, AVC explant rescue experiment, reporter analysis of Snai1 enhancers Cell reports High 28538179
2015 A HAND2 missense mutation (p.L47P) identified in a tetralogy of Fallot patient significantly decreases HAND2 transcriptional activity in reporter assays and markedly reduces synergistic activation between HAND2 and GATA4 or NKX2.5. Sequencing of CHD patients, dual-luciferase reporter assay with wild-type and mutant HAND2 International journal of molecular medicine Medium 26676105
2016 A HAND2 missense mutation (p.S65I) identified in a familial ventricular septal defect pedigree significantly diminishes HAND2 transcriptional activity and abolishes synergistic activation between HAND2 and GATA4 as well as NKX2.5. Sequencing of CHD patients, dual-luciferase reporter assay G3 (Bethesda, Md.) Medium 26865696
2016 Transcription of the lncRNA Upperhand (Uph/Hand2os1) from a promoter within the Hand2 super-enhancer is required to maintain H3K27ac super-enhancer signature and RNA Pol II elongation through the Hand2 enhancer locus; blockade of Uph transcription (not knockdown of the mature transcript) abolishes Hand2 expression and causes right ventricular hypoplasia and embryonic lethality. Promoter deletion knock-in mice, ChIP for H3K27ac, RNA Pol II ChIP, Uph transcript knockdown vs. transcription blockade Nature High 27783597
2019 Hand2 augments chromatin accessibility at loci involved in sarcomere organization, electrical coupling, and membrane depolarization during pacemaker-like reprogramming (iPM formation); a Hand2 cardiac subtype diversity (CSD) domain was identified in the N terminus through biochemical analysis; Hand2 selectively reorganizes chromatin accessibility to promote pacemaker-specific gene expression. ATAC-seq (chromatin accessibility), RNA-seq, biochemical N-terminal domain analysis in fibroblast reprogramming system Cell reports High 31116981
2019 Full-length deletion of Hand2os1 (Uph) lncRNA causes moderate upregulation of HAND2 in hundreds of cardiac cells (single-cell RNA-seq), leading to dysregulated cardiac gene programs, congenital heart defects, and perinatal lethality; short promoter deletion reducing Hand2os1 to 8-32% fails to affect HAND2 expression, indicating the Hand2os1 locus (not transcript) dampens HAND2 expression to restrain cardiomyocyte proliferation. Multiple knockout mouse models (full-length vs. promoter deletion), single-cell RNA sequencing Development (Cambridge, England) High 31273086
2019 HAND2 directly up-regulates IL15 transcription in human endometrial stromal cells (ESCs); ChIP-qPCR shows HAND2 binds a putative HAND2 motif in the upstream region of the human IL15 gene; luciferase reporter assays confirm the upstream region responds to HAND2 transfection, and deletion/substitution of the HAND2 motif abolishes this response. ChIP-qPCR, luciferase reporter assay with motif deletion/substitution, HAND2 overexpression in human ESCs The Journal of biological chemistry High 32444497
2020 Gli3 requires interaction with Hand2 to achieve robust transcriptional activity during mandibular skeletal and glossal development; genomic analysis reveals Gli3 and Hand2 co-occupy regulatory elements for mandibular genes; co-occupied sites contain mandibular-specific low-affinity 'divergent' Gli-binding motifs (dGBMs) that convey synergistic activation of Gli targets in a Hh-signal-independent manner. Mouse genetic analysis (Gli3/Hand2 double mutants), ChIP-seq, reporter gene assays with dGBM motif analysis eLife High 33006313
2021 HAND2 suppresses estrogen signaling in endometrial stroma as a Eutherian innovation allowing blastocyst implantation; HAND2 regulates IL15 expression in decidua and HAND2 promoter loops to an enhancer containing SNPs implicated in gestation length regulation, connecting HAND2 to gestational regulation. Evolutionary transcriptomics, chromatin looping analysis (Hi-C/3C), expression analysis across menstrual cycle and pregnancy eLife Medium 33522483
2022 Hand2 marks mesothelial progenitors in the lateral plate mesoderm; hand2 loss in zebrafish disrupts mesothelium formation with reduced progenitor cells and perturbed migration; single-cell transcriptomics identifies a post-gastrulation hand2 expression signature in distinct LPM progenitor cells, conserved in mouse. Zebrafish genetic loss-of-function, single-cell RNA-seq, time-lapse imaging of hand2 reporter embryos, mouse validation Nature communications High 35354817
2023 HAND2 regulates chromatin accessibility to assist MYCN binding to enhancers in neuroblastoma; HAND2 and MYCN cooperate to compete with nucleosomes to regulate global gene transcription. The cooperative interaction can be targeted with Aurora A kinase inhibitor plus HDAC inhibitor, resulting in potent downregulation of both MYCN and core regulatory circuitry transcription factors. ChIP-seq, ATAC-seq, biochemical/genomic co-occupancy analysis, drug combination treatment in neuroblastoma models Cancer research High 36598365

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nature genetics 563 9171826
2016 Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development. Nature 292 27783597
2004 The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development (Cambridge, England) 276 15576406
1998 A signaling cascade involving endothelin-1, dHAND and msx1 regulates development of neural-crest-derived branchial arch mesenchyme. Development (Cambridge, England) 212 9671575
2000 The bHLH transcription factor dHAND controls Sonic hedgehog expression and establishment of the zone of polarizing activity during limb development. Development (Cambridge, England) 196 10804186
2003 Two endothelin 1 effectors, hand2 and bapx1, pattern ventral pharyngeal cartilage and the jaw joint. Development (Cambridge, England) 187 12588851
2002 Mutual genetic antagonism involving GLI3 and dHAND prepatterns the vertebrate limb bud mesenchyme prior to SHH signaling. Genes & development 186 11850405
2005 Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. Nature genetics 164 15735646
2000 Cardiac expression of the ventricle-specific homeobox gene Irx4 is modulated by Nkx2-5 and dHand. Developmental biology 159 10625552
1998 The bHLH factors, dHAND and eHAND, specify pulmonary and systemic cardiac ventricles independent of left-right sidedness. Developmental biology 157 9576835
2000 Role of dHAND in the anterior-posterior polarization of the limb bud: implications for the Sonic hedgehog pathway. Development (Cambridge, England) 138 10769237
2001 The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation. Developmental biology 136 11784028
2010 Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS genetics 135 20386744
2000 The basic helix-loop-helix transcription factor, dHAND, is required for vascular development. The Journal of clinical investigation 131 10675351
2010 hand2 and Dlx genes specify dorsal, intermediate and ventral domains within zebrafish pharyngeal arches. Development (Cambridge, England) 130 20573696
2001 Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer. Genes & development 130 11711438
2000 The transcription factor dHAND is a downstream effector of BMPs in sympathetic neuron specification. Development (Cambridge, England) 125 10952904
2019 LncRNA HAND2-AS1 promotes liver cancer stem cell self-renewal via BMP signaling. The EMBO journal 124 31334575
2013 Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development. PLoS medicine 122 24265601
2000 A GATA-dependent right ventricular enhancer controls dHAND transcription in the developing heart. Development (Cambridge, England) 120 11076755
2003 Targeted deletion of a branchial arch-specific enhancer reveals a role of dHAND in craniofacial development. Development (Cambridge, England) 118 12571099
2013 Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure. Nature cell biology 116 24161931
2010 Hand2 function in second heart field progenitors is essential for cardiogenesis. Developmental biology 104 21185281
2014 Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration. Development (Cambridge, England) 101 25038045
2014 HAND2 targets define a network of transcriptional regulators that compartmentalize the early limb bud mesenchyme. Developmental cell 96 25453830
2017 Long non-coding RNA HAND2-AS1 inhibits invasion and metastasis in endometrioid endometrial carcinoma through inactivating neuromedin U. Cancer letters 95 29107108
2002 Misexpression of dHAND induces ectopic digits in the developing limb bud in the absence of direct DNA binding. Development (Cambridge, England) 92 12070084
2000 The basic helix-loop-helix transcription factors dHAND and eHAND exhibit dimerization characteristics that suggest complex regulation of function. The Journal of biological chemistry 86 10924525
2018 LncRNA HAND2-AS1 sponging miR-1275 suppresses colorectal cancer progression by upregulating KLF14. Biochemical and biophysical research communications 85 30078677
2007 Hand2 determines the noradrenergic phenotype in the mouse sympathetic nervous system. Developmental biology 83 17531968
2006 The bHLH transcription factor hand2 is essential for noradrenergic differentiation of sympathetic neurons. Development (Cambridge, England) 78 17008447
2000 Conservation of sequence and expression of Xenopus and zebrafish dHAND during cardiac, branchial arch and lateral mesoderm development. Mechanisms of development 76 10906469
2010 Hand2 regulates extracellular matrix remodeling essential for gut-looping morphogenesis in zebrafish. Developmental cell 74 20627079
2011 Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis. Development (Cambridge, England) 73 21558373
2009 Hand2 is required in the epithelium for palatogenesis in mice. Developmental biology 68 19341725
2002 The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer. The Journal of biological chemistry 67 11812799
2021 Mesenchymal stem cell-originated exosomal lncRNA HAND2-AS1 impairs rheumatoid arthritis fibroblast-like synoviocyte activation through miR-143-3p/TNFAIP3/NF-κB pathway. Journal of orthopaedic surgery and research 66 33549125
2011 Hand2 loss-of-function in Hand1-expressing cells reveals distinct roles in epicardial and coronary vessel development. Circulation research 66 21350214
2008 Endoderm-derived Sonic hedgehog and mesoderm Hand2 expression are required for enteric nervous system development in zebrafish. Developmental biology 66 18436202
2010 Hand2 ensures an appropriate environment for cardiac fusion by limiting Fibronectin function. Development (Cambridge, England) 64 20724450
2007 Hand2 is necessary for terminal differentiation of enteric neurons from crest-derived precursors but not for their migration into the gut or for formation of glia. Development (Cambridge, England) 62 17507395
2014 Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium. Cell reports 61 25497097
2008 Cardiac neural crest expression of Hand2 regulates outflow and second heart field development. Circulation research 61 19008477
2019 The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2. Development (Cambridge, England) 58 31273086
2005 Hand2 regulates epithelial formation during myocardial diferentiation. Current biology : CB 58 15786591
2010 Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb. Development (Cambridge, England) 57 20826535
2009 Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. Development (Cambridge, England) 55 19144722
1999 The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas. Laboratory investigation; a journal of technical methods and pathology 55 9952112
2018 Energy stress-induced lncRNA HAND2-AS1 represses HIF1α-mediated energy metabolism and inhibits osteosarcoma progression. American journal of cancer research 51 29637006
2017 HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development. Cell reports 50 28538179
2012 Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos. Development (Cambridge, England) 50 22438573
2003 HAND2 synergistically enhances transcription of dopamine-beta-hydroxylase in the presence of Phox2a. Developmental biology 49 14512028
2019 LncRNA HAND2-AS1 inhibits non-small cell lung cancer migration, invasion and maintains cell stemness through the interactions with TGF-β1. Bioscience reports 48 30509963
2019 LncRNA HAND2-AS1 inhibits 5-fluorouracil resistance by modulating miR-20a/PDCD4 axis in colorectal cancer. Cellular signalling 48 31760170
2019 LncRNA HAND2-AS1 exerts anti-oncogenic effects on ovarian cancer via restoration of BCL2L11 as a sponge of microRNA-340-5p. Journal of cellular physiology 47 31222748
2010 Affinity purification of microRNA-133a with the cardiac transcription factor, Hand2. Proceedings of the National Academy of Sciences of the United States of America 46 20974915
2003 dHAND-Cre transgenic mice reveal specific potential functions of dHAND during craniofacial development. Developmental biology 45 12729557
2015 A novel HAND2 loss-of-function mutation responsible for tetralogy of Fallot. International journal of molecular medicine 44 26676105
2021 Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length. eLife 43 33522483
2018 Long noncoding RNA HAND2-AS1 inhibits cancer cell proliferation, migration, and invasion in esophagus squamous cell carcinoma by regulating microRNA-21. Journal of cellular biochemistry 43 30520131
2009 DNA binding-dependent and -independent functions of the Hand2 transcription factor during mouse embryogenesis. Development (Cambridge, England) 42 19211672
2002 HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy. Biochemical and biophysical research communications 42 12359233
2016 A HAND2 Loss-of-Function Mutation Causes Familial Ventricular Septal Defect and Pulmonary Stenosis. G3 (Bethesda, Md.) 41 26865696
2009 Co-regulated expression of HAND2 and DEIN by a bidirectional promoter with asymmetrical activity in neuroblastoma. BMC molecular biology 38 19348682
2003 The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA. The Journal of biological chemistry 38 14506227
2021 Cardiac-specific overexpression of miR-122 induces mitochondria-dependent cardiomyocyte apoptosis and promotes heart failure by inhibiting Hand2. Journal of cellular and molecular medicine 36 33942477
2020 LncRNA HAND2-AS1 represses cervical cancer progression by interaction with transcription factor E2F4 at the promoter of C16orf74. Journal of cellular and molecular medicine 36 32314545
2013 Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q. Human molecular genetics 35 23449628
2020 The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells. The Journal of biological chemistry 33 32444497
2022 Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma. Nature communications 32 35354817
2004 Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. Journal of cellular biochemistry 32 15486975
2002 Cardiac phenotypes in chromosome 4q- syndrome with and without a deletion of the dHAND gene. Genetics in medicine : official journal of the American College of Medical Genetics 32 12509719
2020 lncRNA HAND2-AS1 Inhibits Liver Cancer Cell Proliferation and Migration by Upregulating SOCS5 to Inactivate the JAK-STAT Pathway. Cancer biotherapy & radiopharmaceuticals 31 32155348
2019 Long non-coding RNA HAND2-AS1 targets glucose metabolism and inhibits cancer cell proliferation in osteosarcoma. Oncology letters 31 31423193
2012 A Phox2- and Hand2-dependent Hand1 cis-regulatory element reveals a unique gene dosage requirement for Hand2 during sympathetic neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 22323723
2001 Human eHAND, but not dHAND, is down-regulated in cardiomyopathies. Journal of molecular and cellular cardiology 31 11549340
2022 NONO enhances mRNA processing of super-enhancer-associated GATA2 and HAND2 genes in neuroblastoma. EMBO reports 30 36416237
2019 LncRNA HAND2-AS1 inhibits proliferation and promotes apoptosis of chronic myeloid leukemia cells by sponging with micRNA-1275. European review for medical and pharmacological sciences 30 30915755
2019 HAND2-AS1 inhibits invasion and metastasis of cervical cancer cells via microRNA-330-5p-mediated LDOC1. Cancer cell international 30 31889905
2010 Transcription factor HAND2 mutations in sporadic Chinese patients with congenital heart disease. Chinese medical journal 30 20819618
2021 HAND2-AS1: A functional cancer-related long non-coding RNA. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 29 33556872
2020 Long Non-Coding RNA HAND2-AS1 Acts as a Tumor Suppressor in High-Grade Serous Ovarian Carcinoma. International journal of molecular sciences 28 32517089
2019 Hand2 Selectively Reorganizes Chromatin Accessibility to Induce Pacemaker-like Transcriptional Reprogramming. Cell reports 27 31116981
2016 Specification of jaw identity by the Hand2 transcription factor. Scientific reports 26 27329940
2020 Long non-coding RNA HAND2-AS1 delays cervical cancer progression via its regulation on the microRNA-21-5p/TIMP3/VEGFA axis. Cancer gene therapy 25 33139818
2019 MicroRNA-92b-3p suppresses angiotensin II-induced cardiomyocyte hypertrophy via targeting HAND2. Life sciences 25 31283925
2020 HAND2-AS1 Inhibits Gastric Adenocarcinoma Cells Proliferation and Aerobic Glycolysis via miRNAs Sponge. Cancer management and research 23 32431548
2020 Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks. eLife 23 33006313
2019 lncRNA HAND2-AS1 inhibits cancer cell proliferation, migration and invasion by downregulating ROCK1 in HPV-positive and negative cervical squamous cell carcinoma. Experimental and therapeutic medicine 23 31555362
2019 Stoichiometric optimization of Gata4, Hand2, Mef2c, and Tbx5 expression for contractile cardiomyocyte reprogramming. Scientific reports 23 31628386
2009 Hand2 regulates chondrogenesis in vitro and in vivo. Bone 23 19932774
2020 LncRNA WTAPP1 promotes cancer cell invasion and migration in NSCLC by downregulating lncRNA HAND2-AS1. BMC pulmonary medicine 22 32473628
2014 Loss of Hand2 in a population of Periostin lineage cells results in pronounced bradycardia and neonatal death. Developmental biology 22 24565998
2013 edn1 and hand2 Interact in early regulation of pharyngeal arch outgrowth during zebrafish development. PloS one 22 23826316
2023 HAND2 Assists MYCN Enhancer Invasion to Regulate a Noradrenergic Neuroblastoma Phenotype. Cancer research 21 36598365
2020 Long noncoding RNA HAND2-AS1 restrains proliferation and metastasis of breast cancer cells through sponging miR-1275 and promoting SOX7. Cancer biomarkers : section A of Disease markers 21 31683462
2016 Distinct roles of hand2 in developing and adult autonomic neurons. Developmental neurobiology 21 26818017
2014 Prenatal alcohol exposure causes the over-expression of DHAND and EHAND by increasing histone H3K14 acetylation in C57 BL/6 mice. Toxicology letters 21 24857828
2021 Long-term, induced expression of Hand2 in peripheral sympathetic neurons ameliorates sarcopenia in geriatric mice. Journal of cachexia, sarcopenia and muscle 20 34546662
2004 JAB1 enhances HAND2 transcriptional activity by regulating HAND2 DNA binding. Journal of neuroscience research 20 15139020

Missed literature

Know a paper Affinage missed for HAND2? Flag it for the maintainers and the community.

No submissions yet.