Hand is the single Drosophila member of the Hand family of class B basic helix-loop-helix (bHLH) transcription factors (ortholog of vertebrate HAND1/HAND2). It is expressed in all cells of the dorsal vessel (cardioblasts and pericardial nephrocytes), in progenitors of the circular visceral muscles, in lymph gland hematopoietic progenitors, garland cells and a few CNS cells. Hand is a direct target of the cardiogenic factors Tinman (NK-2) and Pannier (GATA) in the heart, of Serpent (GATA) in the lymph gland and of Biniou (FoxF) in visceral mesoderm, and is expressed after these determinants, consistent with a role in differentiation rather than specification. Hand is a potent transcriptional activator that, probably as a heterodimer with E-protein (Daughterless) or other bHLH partners, regulates muscle structural genes such as Zasp52 and Msp-300. Loss of Hand causes semilethality, lymph gland deficiency, and abnormal adult hearts (disorganized myofibrils, impaired contractility) and midguts, reflecting a main requirement during pupal remodeling of the larval aorta into the adult heart; whether embryonic heart formation also requires Hand differs between mutant alleles. Hand is also required for wing heart formation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference (Twist/Hand bHLH node) that Hand binds Pol II regulatory region DNA. Hand is a bHLH protein whose basic region is the E-box DNA-binding module; no direct DNA-binding assay for fly Hand is in the cached literature, but it is a potent transcriptional activator in reporter assays. Reason: The bHLH DNA-binding mechanism is shared across the Twist/Hand clade and vertebrate HAND proteins bind E-box/related sites; nothing argues for loss of DNA binding in fly Hand. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Pol II-specific DNA-binding transcription factor activity inferred for the Hand/Twist bHLH clade; fly Hand itself is among the experimental donors (FB:FBgn0032209). Reason: Core molecular function. Hand acts as a potent transcriptional activator and a repressor fusion (Hand-EnR) phenocopies loss of function in heart and lymph gland; Hand regulates muscle structural genes such as Zasp52 and Msp-300. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation PMID:26252215 Drosophila Hand regulates the expression of numerous genes of diverse physiological relevancy, including distinct factors required for proper muscle development and function such as Zasp52 or Msp-300 |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | ACCEPT | Summary: Han et al. 2006 showed that Drosophila Hand is a potent transcriptional activator in reporter assays. Reason: Direct activator assay; the dominant-repressor phenotype supports activation as the in vivo mode of action. Abstract-only cache, but consistent with the curator annotation. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0003700 DNA-binding transcription factor activity | ISS PMID:11404084 New members of the Drosophila Myc transcription factor subfa... | ACCEPT | Summary: Sequence-similarity inference (from Twist) of DNA-binding transcription factor activity, from the genome-wide bHLH survey of Peyrefitte et al. 2001. Reason: Correct but less specific than the Pol II-specific IBA/IDA terms; retained as consistent with the bHLH classification. Supporting Evidence: PMID:11404084 The basic helix-loop-helix (bHLH) proteins represent an evolutionary conserved class of transcription factors PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0005634 nucleus | HDA PMID:26896675 A genome-wide resource for the analysis of protein localisat... | ACCEPT | Summary: Nuclear localization from the genome-wide protein-trap localisation resource. Reason: Consistent with a bHLH transcription factor; corroborated by the IDA annotation. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization inferred for the Hand/Twist bHLH clade. Reason: Expected location of a transcription factor; supported by direct observation. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0005634 nucleus | IC PMID:11404084 New members of the Drosophila Myc transcription factor subfa... | ACCEPT | Summary: Nucleus inferred by curator from the DNA-binding transcription factor activity annotation. Reason: Valid inference; redundant with IDA/HDA evidence. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0005634 nucleus | IDA PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | ACCEPT | Summary: Han et al. 2006 observed Hand protein in nuclei of cardiac and lymph gland cells. Reason: Direct observation; consistent with transcription factor function. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic mapping from UniProt subcellular location (nucleus). Reason: Correct; consistent with experimental evidence. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0006355 regulation of DNA-templated transcription | ISS PMID:11404084 New members of the Drosophila Myc transcription factor subfa... | MODIFY | Summary: Regulation of DNA-templated transcription inferred by similarity to Twist. Reason: Correct but too general; experimental data show Hand activates Pol II transcription of target genes, so positive regulation of transcription by RNA polymerase II is the informative term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation PMID:26252215 Drosophila Hand regulates the expression of numerous genes of diverse physiological relevancy, including distinct factors required for proper muscle development and function such as Zasp52 or Msp-300 |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of transcription by RNA polymerase II inferred for the Hand/Twist clade. Reason: Correct process for a Pol II DNA-binding transcription factor; the IBA level is appropriate. Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation PMID:26252215 Drosophila Hand regulates the expression of numerous genes of diverse physiological relevancy, including distinct factors required for proper muscle development and function such as Zasp52 or Msp-300 |
| GO:0007508 larval heart development | IMP PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | ACCEPT | Summary: Hand mutants (homologous recombination null) have hypoplastic myocardium, reduced pericardial cells and cardiac apoptosis; cardiac Hand expression rescues lethality. Reason: Heart development is the best-established in vivo role of Hand, and the module annotates Hand to heart development. Note that Lo et al. 2007 report a normal embryonic dorsal vessel in their null allele but abnormal adult hearts, so the larval/adult heart requirement is the robust part. Supporting Evidence: PMID:16467358 Disruption of Hand function by homologous recombination also results in profound cardiac defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic cells, accompanied by cardiac apoptosis PMID:17904115 homozygous adult flies lacking Hand possess morphologically abnormal dorsal vessels characterized by a disorganized myofibrillar structure, reduced systolic and diastolic diameter, and abnormal heartbeat contractions |
| GO:0030097 hemopoiesis | IMP PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | ACCEPT | Summary: Hand loss of function causes deficiency of lymph gland hematopoietic progenitors; Hand is a direct target of Serpent in the lymph gland. Reason: Independently supported by Lo et al. 2007 (lymph glands missing in a large fraction of null embryos), making this one of the reproducible Hand phenotypes. Supporting Evidence: PMID:16467358 reveal a previously unrecognized requirement of Hand genes in hematopoiesis PMID:17904115 The dorsal vessel and midgut musculature are unaffected in null mutant embryos, but in a large fraction the lymph glands are missing PMID:15975941 Hand is activated by Tinman and Pannier in cardioblasts and pericardial nephrocytes, and by Serpent in hematopoietic progenitors in the lymph gland |
| GO:0032502 developmental process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Very general developmental process inferred for the bHLH clade. Reason: True but uninformative; more specific heart, lymph gland and hemopoiesis terms capture the biology. Supporting Evidence: PMID:16467358 Disruption of Hand function by homologous recombination also results in profound cardiac defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic cells, accompanied by cardiac apoptosis |
| GO:0032968 positive regulation of transcription elongation by RNA polymerase II | IDA PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | MODIFY | Summary: Positive regulation of transcription elongation, apparently derived from the transcriptional activation assays of Han et al. 2006. Reason: Reporter activation assays show that Hand activates transcription but do not distinguish elongation from initiation; nothing in the available evidence indicates an elongation-specific mechanism. Positive regulation of transcription by RNA polymerase II captures the finding. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:16467358 Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation |
| GO:0035050 embryonic heart tube development | IMP PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | KEEP AS NON CORE | Summary: Han et al. 2006 report hypoplastic myocardium and loss of pericardial cells in Hand mutant embryos. Reason: The embryonic heart phenotype is contested: Lo et al. 2007 found the dorsal vessel unaffected in null mutant embryos and placed the main Hand requirement in pupal remodeling of the adult heart. The curator annotation is retained, but the embryonic heart tube role is not treated as core. Supporting Evidence: PMID:16467358 Disruption of Hand function by homologous recombination also results in profound cardiac defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic cells, accompanied by cardiac apoptosis PMID:17904115 The dorsal vessel and midgut musculature are unaffected in null mutant embryos, but in a large fraction the lymph glands are missing |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:16467358 Hand, an evolutionarily conserved bHLH transcription factor ... | KEEP AS NON CORE | Summary: Cardiac apoptosis accompanies loss of Hand, and expression of the caspase inhibitor P35 partially rescues the cardiac and lymph gland phenotypes. Reason: Likely an indirect consequence of failed cardiac/hematopoietic differentiation rather than a dedicated anti-apoptotic function; retained as non-core. Supporting Evidence: PMID:16467358 Disruption of Hand function by homologous recombination also results in profound cardiac defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic cells, accompanied by cardiac apoptosis PMID:16467358 cardiac expression of a human HAND gene, or the caspase inhibitor P35, partially rescued the cardiac and lymph gland phenotypes |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | ACCEPT | Summary: Protein dimerization activity from the HLH domain InterPro mapping. Reason: bHLH proteins act as dimers; Daughterless and Nautilus were identified genetically as candidate Hand dimerization partners in the wing hearts. Supporting Evidence: PMID:23747982 we identified Daughterless and Nautilus as potential dimerization partners of Hand in wing hearts |
| GO:0048813 dendrite morphogenesis | IMP PMID:23977298 Functional genomic analyses of two morphologically distinct ... | KEEP AS NON CORE | Summary: Large-scale RNAi screen of transcription factors in class I/IV dendritic arborization neurons; Hand knockdown was among the hits affecting dendrite morphology. Reason: Screen-level RNAi evidence in sensory neurons; Hand is expressed in a few CNS cells but has no characterized neuronal function. Retained as non-core pending confirmation with mutant alleles. Supporting Evidence: PMID:23977298 35 of the 37 TFs (∼95%) tested in C-IV neurons resulted in robust and consistent dendritic defects in at least 2 independent UAS-IR lines PMID:12424518 We found hand to be expressed in the entire heart, including all cardioblasts and pericardial cells, in the progenitors of the circular visceral muscles, the lymph gland and garland cells, and in a few cells in the CNS |
| GO:0007512 adult heart development | IMP PMID:17904115 The Drosophila Hand gene is required for remodeling of the d... | NEW | Summary: Hand null adults have disorganized myofibrils, reduced systolic and diastolic diameter and abnormal heartbeat; Hand is required for the hormone-dependent remodeling of the larval aorta into the adult heart. Hand is also required for wing heart formation. Reason: Hand is a transcription factor expressed in the dorsal vessel that directly regulates cardiac muscle genes, so involvement in the adult heart developmental process follows standard TF-in-process convention. This is the most robust heart phenotype across alleles and is not represented in GOA. Supporting Evidence: PMID:17904115 Hand participates in the proper hormone-dependent remodeling of the larval aorta into the adult heart PMID:17904115 homozygous adult flies lacking Hand possess morphologically abnormal dorsal vessels characterized by a disorganized myofibrillar structure, reduced systolic and diastolic diameter, and abnormal heartbeat contractions PMID:26252215 Drosophila Hand regulates the expression of numerous genes of diverse physiological relevancy, including distinct factors required for proper muscle development and function such as Zasp52 or Msp-300 |
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Download this section (compressed HTML)Q: Is Hand required for embryonic dorsal vessel formation (Han et al. 2006) or only for its pupal remodeling (Lo et al. 2007)? Do the differing alleles or genetic backgrounds explain the discrepancy?
Q: What are the direct (bound) Hand target genes in cardioblasts and visceral muscle, and which E-box variants and dimerization partners (Daughterless, Nautilus, Twist) does Hand use in vivo?
Experiment: Hand CUT&RUN or ChIP-seq in larval/pupal dorsal vessel combined with RNA-seq of conditional Hand knockdown to define direct targets (e.g. Zasp52, Msp-300) and test E-box dependence of their enhancers.
Experiment: Side-by-side phenotyping of the Han et al. and Lo et al. Hand null alleles in a common genetic background with cardioblast and pericardial markers to resolve the embryonic heart requirement.
Hand (Hand) encodes a transcription factor that contributes to cardiogenesis, hemopoiesis, and muscle function.
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