TBX20 is a T-box family sequence-specific DNA-binding transcription factor expressed in cardiac progenitors, myocardium and endocardium (including endocardial cushions), and in hindbrain branchiomotor/visceromotor neurons. Through its T-box domain it binds brachyury-like half sites and acts as a context-dependent activator or repressor of RNA polymerase II target genes; the long isoform carries C-terminal transactivation and transrepression domains. TBX20 physically cooperates with NKX2-5, GATA4/5, TBX5 and ISL1 to activate cardiac enhancers (e.g. NPPA, GJA5, MEF2C, NKX2-5), and represses TBX2 in prospective chamber myocardium, partly by binding SMAD1/5 and blocking BMP/SMAD-dependent activation. In mouse it is required for heart tube elongation, chamber formation, atrioventricular canal and valve development and cardiomyocyte proliferation, and continues to maintain ion channel and contractile gene programs in adult cardiomyocytes. Human TBX20 variants cause atrial septal defect 4 and are associated with valve defects, tetralogy of Fallot and dilated cardiomyopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer from mouse Tbx20 for negative regulation of Pol II transcription. Reason: TBX20 acts as a context-dependent transcriptional repressor; in mouse it represses Tbx2 in prospective chamber myocardium and ChIP-seq/RNA-seq in adult heart identified directly repressed targets. Repression is one of the two documented transcriptional outputs and is supported by the long isoform's C-terminal repression domain. Supporting Evidence: PMID:15843414 Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: BHF-UCL ISS from mouse Tbx20 for negative regulation of Pol II transcription. Reason: TBX20 acts as a context-dependent transcriptional repressor; in mouse it represses Tbx2 in prospective chamber myocardium and ChIP-seq/RNA-seq in adult heart identified directly repressed targets. Supporting Evidence: PMID:15843414 Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0000785 chromatin | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PAINT) chromatin localization for T-box family TFs. Reason: Sequence-specific DNA-binding T-box factor that occupies cis-regulatory regions in chromatin (ChIP-seq in adult heart; ChIP on the Nppa enhancer). Supporting Evidence: PMID:22328084 The TBX20 DNA-binding motif that we uncovered from our ChIP data ( 14 ) (consensus AGGTGNTGACAG) resembles known T-box DNA-binding motifs identified in vitro PMID:19762328 revealed significantly enhanced occupancy of the I121M, on the Nppa promoter |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based ISA chromatin annotation for a sequence-specific DNA-binding TF. Reason: Sequence-specific DNA-binding T-box factor that occupies cis-regulatory regions in chromatin (ChIP-seq in adult heart; ChIP on the Nppa enhancer). Supporting Evidence: PMID:22328084 The TBX20 DNA-binding motif that we uncovered from our ChIP data ( 14 ) (consensus AGGTGNTGACAG) resembles known T-box DNA-binding motifs identified in vitro |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:19762328 A gain-of-function TBX20 mutation causes congenital atrial s... | ACCEPT | Summary: IDA from Posch et al. 2010: SPR of the TBX20 T-box on T-half sites and ChIP occupancy of the Nppa promoter by human/mouse TBX20. Reason: TBX20 binds T-box half-site DNA via its T-box domain; human TBX20 occupies the Nppa promoter enhancer in ChIP, and in vivo ChIP-seq in mouse heart defined a TBX20 motif near Pol II-transcribed target genes. Supporting Evidence: PMID:19762328 revealed significantly enhanced occupancy of the I121M, on the Nppa promoter PMID:19762328 Occupancy of DNA binding sites on target genes was also increased |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer from mouse (IDA, Stennard 2003) for Pol II regulatory region sequence-specific DNA binding. Reason: TBX20 binds T-box half-site DNA via its T-box domain; human TBX20 occupies the Nppa promoter enhancer in ChIP, and in vivo ChIP-seq in mouse heart defined a TBX20 motif near Pol II-transcribed target genes. Supporting Evidence: PMID:14550786 Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site PMID:22328084 The TBX20 DNA-binding motif that we uncovered from our ChIP data ( 14 ) (consensus AGGTGNTGACAG) resembles known T-box DNA-binding motifs identified in vitro |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for Pol II cis-regulatory region sequence-specific DNA binding across T-box family. Reason: TBX20 binds T-box half-site DNA via its T-box domain; human TBX20 occupies the Nppa promoter enhancer in ChIP, and in vivo ChIP-seq in mouse heart defined a TBX20 motif near Pol II-transcribed target genes. Supporting Evidence: PMID:14550786 Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site PMID:22328084 The TBX20 DNA-binding motif that we uncovered from our ChIP data ( 14 ) (consensus AGGTGNTGACAG) resembles known T-box DNA-binding motifs identified in vitro |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (T-box InterPro + ortholog) for cis-regulatory region sequence-specific DNA binding. Reason: TBX20 binds T-box half-site DNA via its T-box domain; human TBX20 occupies the Nppa promoter enhancer in ChIP, and in vivo ChIP-seq in mouse heart defined a TBX20 motif near Pol II-transcribed target genes. Supporting Evidence: PMID:14550786 Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for DNA-binding TF activity, Pol II-specific, propagated across the T-box family. Reason: Core molecular function: TBX20 is a sequence-specific Pol II DNA-binding transcription factor that activates (e.g. Nppa, Gja5, Mef2c and Nkx2-5 enhancers, with NKX2-5/GATA4/ISL1) or represses target genes depending on context and isoform. Consistent with the cardiac specification module annoton (GO:0000981). Supporting Evidence: PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor PMID:15843409 Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:19762328 A gain-of-function TBX20 mutation causes congenital atrial s... | ACCEPT | Summary: IDA from Posch et al. 2010 (luciferase reporter and ChIP with human/mouse TBX20 on Nppa and Gja5 enhancers). Reason: Core molecular function: TBX20 is a sequence-specific Pol II DNA-binding transcription factor that activates (e.g. Nppa, Gja5, Mef2c and Nkx2-5 enhancers, with NKX2-5/GATA4/ISL1) or represses target genes depending on context and isoform. Consistent with the cardiac specification module annoton (GO:0000981). Supporting Evidence: PMID:19762328 Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5 PMID:19762328 revealed significantly enhanced occupancy of the I121M, on the Nppa promoter |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer from mouse Tbx20. Reason: Core molecular function: TBX20 is a sequence-specific Pol II DNA-binding transcription factor that activates (e.g. Nppa, Gja5, Mef2c and Nkx2-5 enhancers, with NKX2-5/GATA4/ISL1) or represses target genes depending on context and isoform. Consistent with the cardiac specification module annoton (GO:0000981). Supporting Evidence: PMID:14550786 Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based ISA (T-box family 6.5.3). Reason: Core molecular function: TBX20 is a sequence-specific Pol II DNA-binding transcription factor that activates (e.g. Nppa, Gja5, Mef2c and Nkx2-5 enhancers, with NKX2-5/GATA4/ISL1) or represses target genes depending on context and isoform. Consistent with the cardiac specification module annoton (GO:0000981). Supporting Evidence: PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer from mouse (IDA, Stennard 2003) for Pol II-specific activator activity. Reason: TBX20 synergistically activates cardiac enhancers (Nppa, Gja5, Mef2c AHF, Nkx2-5) together with NKX2-5, GATA4/5 and ISL1. It is also a repressor in other contexts, so activator activity is one context-dependent face of its TF activity. Supporting Evidence: PMID:14550786 Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression PMID:15843409 Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0001706 endoderm formation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from Xenopus tbx20 for endoderm formation. Reason: The Xenopus source (Stennard 2003) showed that ectopic overexpression of Tbx20a induced mesodermal and endodermal markers in Xenopus embryos. Gain-of-function induction of markers is not evidence that TBX20 normally participates in germ layer formation; no loss-of-function data support a role for TBX20 in endoderm or lateral mesoderm formation, and TBX20 expression begins in the cardiac crescent after gastrulation. Supporting Evidence: PMID:14550786 enforced expression of Tbx20a, but not Tbx20b, led to induction of mesodermal and endodermal lineage markers as well as cell migration |
| GO:0001708 cell fate specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for cell fate specification (T-box family; seeded by fly H15/mid and mouse T-box genes). Reason: Plausible at the family level (fly H15/midline specify cardioblast fates); for TBX20 the closest supported role is in the chamber vs non-chamber myocardial lineage split via Tbx2 repression. Developmental, non-core. Supporting Evidence: PMID:15843414 Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program |
| GO:0001947 heart looping | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for heart looping. Reason: Tbx20 mutant mouse hearts fail to loop, but this appears secondary to the failure of chamber formation and heart-tube elongation; keep as a non-core developmental outcome. Supporting Evidence: PMID:15901664 dorsoventral patterning of the tube, formation of working myocardium, looping, and further differentiation and morphogenesis fail |
| GO:0001947 heart looping | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (IMP Singh 2005/Takeuchi 2005) for heart looping. Reason: Tbx20 mutant mouse hearts fail to loop, but this appears secondary to the failure of chamber formation and heart-tube elongation; keep as a non-core developmental outcome. Supporting Evidence: PMID:15901664 dorsoventral patterning of the tube, formation of working myocardium, looping, and further differentiation and morphogenesis fail |
| GO:0003143 embryonic heart tube morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for embryonic heart tube morphogenesis. Reason: Tbx20-null mouse embryos form a linear heart tube that fails to elongate and progress to a chambered heart. Supported, but the more specific term embryonic heart tube elongation (GO:0036306) better captures the defect. Supporting Evidence: PMID:15901664 The tube does not elongate, indicating a defect in recruitment of mesenchyme from the secondary heart field |
| GO:0003143 embryonic heart tube morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for embryonic heart tube morphogenesis. Reason: Tbx20-null mouse embryos form a linear heart tube that fails to elongate and progress to a chambered heart. Supported, but the more specific term embryonic heart tube elongation (GO:0036306) better captures the defect. Supporting Evidence: PMID:15901664 The tube does not elongate, indicating a defect in recruitment of mesenchyme from the secondary heart field |
| GO:0003148 outflow tract septum morphogenesis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA (ARBA/ortholog) for outflow tract septum morphogenesis. Reason: Graded Tbx20 knockdown in mouse caused outflow tract hypoplasia and persistent truncus arteriosus (failed OFT septation); TBX20 variants are found in human TOF. A real developmental requirement, but downstream of TBX20's core TF activity in second heart field-derived myocardium. Supporting Evidence: PMID:15843409 A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle |
| GO:0003148 outflow tract septum morphogenesis | IMP PMID:18275040 Characterization of TBX20 in human hearts and its regulation... | KEEP AS NON CORE | Summary: BHF-UCL IMP from Hammer et al. 2008 (TBX20 in human TOF hearts). The cached abstract (abstract only) reports no disease-causing mutations but TBX20 upregulation in TOF biopsies; the curator saw the full text. Reason: Graded Tbx20 knockdown in mouse caused outflow tract hypoplasia and persistent truncus arteriosus (failed OFT septation); TBX20 variants are found in human TOF. A real developmental requirement, but downstream of TBX20's core TF activity in second heart field-derived myocardium. The human evidence in this paper is expression association; we defer to the curator given the strong mouse support for the process. Supporting Evidence: PMID:18275040 TBX20 is significantly upregulated in tissue samples of patients with TOF, but not VSD PMID:18275040 In animal studies Tbx20 is essential for the development of the atrioventricular channel, the outflow tract and valves PMID:15843409 A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle |
| GO:0003148 outflow tract septum morphogenesis | IMP PMID:18834961 T-box transcription factor TBX20 mutations in Chinese patien... | KEEP AS NON CORE | Summary: BHF-UCL IMP from Liu et al. 2008 (TBX20 missense variants in Chinese CHD patients, including TOF; abstract only). Reason: Graded Tbx20 knockdown in mouse caused outflow tract hypoplasia and persistent truncus arteriosus (failed OFT septation); TBX20 variants are found in human TOF. A real developmental requirement, but downstream of TBX20's core TF activity in second heart field-derived myocardium. Supporting Evidence: PMID:18834961 they probably contribute to the risk of atrial septal defect (ASD), total anomalous pulmonary venous connection (TAPVC) and tetralogy of Fallot (TOF) in a small subset of Chinese PMID:15843409 A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle |
| GO:0003151 outflow tract morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer (mouse IMP, Takeuchi 2005) for outflow tract morphogenesis. Reason: Graded Tbx20 knockdown in mouse caused outflow tract hypoplasia and persistent truncus arteriosus (failed OFT septation); TBX20 variants are found in human TOF. A real developmental requirement, but downstream of TBX20's core TF activity in second heart field-derived myocardium. Supporting Evidence: PMID:15843409 including hypoplasia of the outflow tract and right ventricle, which derive from the anterior heart field (AHF) PMID:15843409 A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle |
| GO:0003171 atrioventricular valve development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for AV valve development. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed |
| GO:0003171 atrioventricular valve development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (IMP, Cai 2011) for AV valve development. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed |
| GO:0003175 tricuspid valve development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer (mouse IMP, Takeuchi 2005) for tricuspid valve development. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003175 tricuspid valve development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for tricuspid valve development. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003176 aortic valve development | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA for aortic valve development. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003179 heart valve morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA for heart valve morphogenesis. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation PMID:17064679 these data support a role for Tbx20 in repressing extracellular matrix remodeling and promoting cell proliferation in mesenchymal valve precursor populations in endocardial cushions |
| GO:0003180 aortic valve morphogenesis | IMP PMID:18275040 Characterization of TBX20 in human hearts and its regulation... | KEEP AS NON CORE | Summary: BHF-UCL IMP from Hammer et al. 2008 (abstract only; TBX20 expression in human TOF hearts). Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. The cached abstract does not itself describe valve phenotypes; we defer to the curator who read the full text. Supporting Evidence: PMID:18275040 In animal studies Tbx20 is essential for the development of the atrioventricular channel, the outflow tract and valves PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003180 aortic valve morphogenesis | IMP PMID:18834961 T-box transcription factor TBX20 mutations in Chinese patien... | KEEP AS NON CORE | Summary: BHF-UCL IMP from Liu et al. 2008 (TBX20 variants in Chinese CHD patients; abstract only). Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:18834961 they probably contribute to the risk of atrial septal defect (ASD), total anomalous pulmonary venous connection (TAPVC) and tetralogy of Fallot (TOF) in a small subset of Chinese PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003193 pulmonary valve formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for pulmonary valve formation. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003193 pulmonary valve formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for pulmonary valve formation. Reason: Tbx20 is required in mouse for valve formation (knockdown) and is expressed at high levels in endocardial cushions where it promotes valve-precursor mesenchyme proliferation; human TBX20 variants cause valve defects. Developmental outcome, non-core. Supporting Evidence: PMID:15843409 demonstrated a critical requirement for Tbx20 in valve formation |
| GO:0003203 endocardial cushion morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for endocardial cushion morphogenesis. Reason: Tbx20 is expressed in endocardial cushions, myocardial Tbx20 is required for AVC endocardial EMT via Bmp2, and Tbx20 promotes cushion mesenchyme proliferation and represses ECM remodeling genes. Developmental, non-core. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed PMID:17064679 these data support a role for Tbx20 in repressing extracellular matrix remodeling and promoting cell proliferation in mesenchymal valve precursor populations in endocardial cushions |
| GO:0003203 endocardial cushion morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for endocardial cushion morphogenesis. Reason: Tbx20 is expressed in endocardial cushions, myocardial Tbx20 is required for AVC endocardial EMT via Bmp2, and Tbx20 promotes cushion mesenchyme proliferation and represses ECM remodeling genes. Developmental, non-core. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed PMID:17064679 these data support a role for Tbx20 in repressing extracellular matrix remodeling and promoting cell proliferation in mesenchymal valve precursor populations in endocardial cushions |
| GO:0003207 cardiac chamber formation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse (IMP Singh 2005) for cardiac chamber formation. Reason: A defining, well-replicated requirement: Tbx20-null mouse hearts fail to progress to a multi-chambered heart, with ectopic Tbx2 throughout the heart tube. Chamber formation is the central developmental output of TBX20's TF activity. Supporting Evidence: PMID:15901664 Tbx20 is required for progression from the linear heart tube to a multi-chambered heart PMID:15843414 Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program |
| GO:0003215 cardiac right ventricle morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for cardiac right ventricle morphogenesis. Reason: Tbx20 knockdown causes hypoplastic right ventricle (anterior heart field derivative), with decreased Nkx2-5 and Mef2c. Developmental, non-core. Supporting Evidence: PMID:15843409 including hypoplasia of the outflow tract and right ventricle, which derive from the anterior heart field (AHF) |
| GO:0003215 cardiac right ventricle morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for cardiac right ventricle morphogenesis. Reason: Tbx20 knockdown causes hypoplastic right ventricle (anterior heart field derivative), with decreased Nkx2-5 and Mef2c. Developmental, non-core. Supporting Evidence: PMID:15843409 including hypoplasia of the outflow tract and right ventricle, which derive from the anterior heart field (AHF) |
| GO:0003272 endocardial cushion formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for endocardial cushion formation. Reason: Tbx20 is expressed in endocardial cushions, myocardial Tbx20 is required for AVC endocardial EMT via Bmp2, and Tbx20 promotes cushion mesenchyme proliferation and represses ECM remodeling genes. Developmental, non-core. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed |
| GO:0003272 endocardial cushion formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for endocardial cushion formation. Reason: Tbx20 is expressed in endocardial cushions, myocardial Tbx20 is required for AVC endocardial EMT via Bmp2, and Tbx20 promotes cushion mesenchyme proliferation and represses ECM remodeling genes. Developmental, non-core. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed |
| GO:0003279 cardiac septum development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for cardiac septum development. Reason: Septation defects (ASD, PFO, truncus arteriosus) are hallmark phenotypes of TBX20 loss in human and mouse; general parent of the more specific atrial septum morphogenesis annotation. Supporting Evidence: PMID:17668378 associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis PMID:15843409 A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle |
| GO:0003279 cardiac septum development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for cardiac septum development. Reason: Septation defects (ASD, PFO, truncus arteriosus) are hallmark phenotypes of TBX20 loss in human and mouse; general parent of the more specific atrial septum morphogenesis annotation. Supporting Evidence: PMID:17668378 associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis PMID:15843409 A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle |
| GO:0003344 pericardium morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for pericardium morphogenesis. Reason: Derived from the mouse Tbx20-null phenotype (Singh 2005, MGI IMP). Pericardial abnormalities in a mid-gestation lethal heart mutant with hemodynamic failure are likely secondary; we cannot verify a direct role from the abstract. Non-core at best. Supporting Evidence: PMID:15901664 Tbx20 is required for progression from the linear heart tube to a multi-chambered heart |
| GO:0003344 pericardium morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for pericardium morphogenesis. Reason: Derived from the mouse Tbx20-null phenotype (Singh 2005, MGI IMP). Pericardial abnormalities in a mid-gestation lethal heart mutant with hemodynamic failure are likely secondary; we cannot verify a direct role from the abstract. Non-core at best. Supporting Evidence: PMID:15901664 Tbx20 is required for progression from the linear heart tube to a multi-chambered heart |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer for DNA binding. Reason: Correct but general; TBX20 binds DNA through its T-box. More specific sequence-specific DNA binding terms are also present. Supporting Evidence: PMID:14550786 Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (InterPro T-box) for DNA-binding TF activity. Reason: Core molecular function: TBX20 is a sequence-specific Pol II DNA-binding transcription factor that activates (e.g. Nppa, Gja5, Mef2c and Nkx2-5 enhancers, with NKX2-5/GATA4/ISL1) or represses target genes depending on context and isoform. Consistent with the cardiac specification module annoton (GO:0000981). Supporting Evidence: PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus. Reason: T-box transcription factor acting in the nucleus; UniProt nuclear localization is by PROSITE rule and mouse Tbx20 is nuclear in transfected cells. Supporting Evidence: PMID:19762328 revealed significantly enhanced occupancy of the I121M, on the Nppa promoter |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA nucleus. Reason: T-box transcription factor acting in the nucleus; UniProt nuclear localization is by PROSITE rule and mouse Tbx20 is nuclear in transfected cells. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse (IDA Stennard 2003) for nucleus. Reason: T-box transcription factor acting in the nucleus; UniProt nuclear localization is by PROSITE rule and mouse Tbx20 is nuclear in transfected cells. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for cytoplasm. Reason: Mouse Tbx20 was observed in cytoplasm in transfection/localization studies (Stennard 2003; Singh 2009 showed Tbx20 interacting with Smad1/5). The functional site of action is the nucleus; cytoplasmic presence is not a defining feature. Supporting Evidence: PMID:19661464 both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4 |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for cytoplasm. Reason: Mouse Tbx20 was observed in cytoplasm in transfection/localization studies (Stennard 2003; Singh 2009 showed Tbx20 interacting with Smad1/5). The functional site of action is the nucleus; cytoplasmic presence is not a defining feature. Supporting Evidence: PMID:19661464 both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4 |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA for regulation of DNA-templated transcription. Reason: Correct, general parent of the Pol II-specific regulation terms. Supporting Evidence: PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for regulation of transcription by RNA polymerase II. Reason: Correct; TBX20 directly regulates Pol II target genes as activator and repressor. Supporting Evidence: PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor PMID:22328084 The TBX20 DNA-binding motif that we uncovered from our ChIP data ( 14 ) (consensus AGGTGNTGACAG) resembles known T-box DNA-binding motifs identified in vitro |
| GO:0009953 dorsal/ventral pattern formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (Singh 2005) for dorsal/ventral pattern formation. Reason: Dorsoventral patterning of the heart tube fails in Tbx20-null mice; this is a cardiac patterning outcome rather than an embryonic axis role. Non-core. Supporting Evidence: PMID:15901664 dorsoventral patterning of the tube, formation of working myocardium, looping, and further differentiation and morphogenesis fail |
| GO:0010718 positive regulation of epithelial to mesenchymal transition | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer (mouse IMP, Cai 2011) for positive regulation of EMT. Reason: Myocardial Tbx20 is required non-cell-autonomously for AVC endocardial EMT, acting through maintenance of Bmp2 expression; an indirect, developmental regulatory role. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed PMID:21983003 re-expression of Bmp2 in the AVC myocardium substantially rescues the EMT defects resulting from the lack of Tbx20, suggesting Bmp2 is one of the key downstream targets of Tbx20 in AVC development |
| GO:0014031 mesenchymal cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for mesenchymal cell development. Reason: Based on the endocardial EMT defect in myocardial Tbx20 mutants (Cai 2011). The role is indirect (via myocardial Bmp2); non-core. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed PMID:21983003 re-expression of Bmp2 in the AVC myocardium substantially rescues the EMT defects resulting from the lack of Tbx20, suggesting Bmp2 is one of the key downstream targets of Tbx20 in AVC development |
| GO:0014031 mesenchymal cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for mesenchymal cell development. Reason: Based on the endocardial EMT defect in myocardial Tbx20 mutants (Cai 2011). The role is indirect (via myocardial Bmp2); non-core. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed |
| GO:0021524 visceral motor neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for visceral motor neuron differentiation. Reason: Tbx20 is expressed in branchiomotor/visceromotor neurons; mouse knockdown altered Isl2/Hb9 and conditional deletion disrupted motor neuron cell body migration, while initial generation of BM/VM neurons was normal. A genuine non-cardiac role of the TF, non-core relative to heart function. Supporting Evidence: PMID:15843409 an intermediate knockdown revealed a role for Tbx20 in motoneuron development, specifically in the regulation of the transcription factors Isl2 and Hb9 PMID:17119020 Tbx20 was required for the tangential (caudal) migration of facial neurons |
| GO:0021524 visceral motor neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for visceral motor neuron differentiation. Reason: Tbx20 is expressed in branchiomotor/visceromotor neurons; mouse knockdown altered Isl2/Hb9 and conditional deletion disrupted motor neuron cell body migration, while initial generation of BM/VM neurons was normal. A genuine non-cardiac role of the TF, non-core relative to heart function. Supporting Evidence: PMID:15843409 an intermediate knockdown revealed a role for Tbx20 in motoneuron development, specifically in the regulation of the transcription factors Isl2 and Hb9 PMID:17119020 Tbx20 was required for the tangential (caudal) migration of facial neurons |
| GO:0030513 positive regulation of BMP signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse (Cai 2011) for positive regulation of BMP signaling pathway. Reason: Myocardial Tbx20 maintains Bmp2 expression in the AVC, so TBX20 acts upstream of BMP signaling. However, in chamber myocardium Tbx20 attenuates Bmp/Smad signaling by sequestering Smad1/5; the net effect on the pathway is context-dependent. Indirect, non-core. Supporting Evidence: PMID:21983003 re-expression of Bmp2 in the AVC myocardium substantially rescues the EMT defects resulting from the lack of Tbx20, suggesting Bmp2 is one of the key downstream targets of Tbx20 in AVC development PMID:19661464 both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4 |
| GO:0035922 foramen ovale closure | IMP PMID:19762328 A gain-of-function TBX20 mutation causes congenital atrial s... | KEEP AS NON CORE | Summary: BHF-UCL IMP from Posch et al. 2010: TBX20 I121M carriers show large patent foramen ovale. Reason: Human genetic evidence links TBX20 variants to PFO; this is a developmental/anatomical outcome downstream of TBX20 TF activity in atrial septation. Non-core. Supporting Evidence: PMID:19762328 Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects |
| GO:0036302 atrioventricular canal development | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer (mouse IMP Cai 2011) for AV canal development. Reason: Myocardial Tbx20 is required for AVC constriction and endocardial EMT; Tbx20 also confines Tbx2 to the AVC. AVC development is a central, well-supported output of TBX20 in chamber/non-chamber patterning. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed PMID:19661464 both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4 |
| GO:0036302 atrioventricular canal development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse for AV canal development. Reason: Myocardial Tbx20 is required for AVC constriction and endocardial EMT; Tbx20 also confines Tbx2 to the AVC. AVC development is a central, well-supported output of TBX20 in chamber/non-chamber patterning. Supporting Evidence: PMID:21983003 mice lacking Tbx20 in the AVC myocardium fail to form the AVC constriction, and the endocardial epithelial-mesenchymal transition (EMT) is severely perturbed |
| GO:0036306 embryonic heart tube elongation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer (mouse IMP Singh 2005) for embryonic heart tube elongation. Reason: Tbx20-null heart tubes fail to elongate, reflecting defective addition of second heart field cells; a primary, specific developmental requirement. Supporting Evidence: PMID:15901664 The tube does not elongate, indicating a defect in recruitment of mesenchyme from the secondary heart field |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl ortholog transfer from a rat IMP (Liu et al. 2016, PMID:27572266) for positive regulation of apoptotic process. Reason: The source paper reports that silencing TBX20 induced apoptosis in H9c2 rat cardiomyoblasts and HEK293 cells, which if anything implies that TBX20 suppresses apoptosis, the opposite direction of the annotated term. The underlying evidence is a single cell-line knockdown study, and no in vivo data support a pro-apoptotic role. The transferred annotation is contradicted by its own source. Supporting Evidence: PMID:27572266 Silencing of TBX20 in H9c2 and HEK293 cells significantly inhibited cell proliferation, induced cell apoptosis and led to G2/M cell cycle arrest |
| GO:0045892 negative regulation of DNA-templated transcription | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse for negative regulation of DNA-templated transcription. Reason: TBX20 acts as a context-dependent transcriptional repressor; in mouse it represses Tbx2 in prospective chamber myocardium and ChIP-seq/RNA-seq in adult heart identified directly repressed targets. Supporting Evidence: PMID:15843414 Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program PMID:22328084 This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA for positive regulation of DNA-templated transcription. Reason: TBX20 activates cardiac target genes (with NKX2-5/GATA4/ISL1); correct general term. Supporting Evidence: PMID:15843409 Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer (mouse IDA Stennard 2003) for positive regulation of Pol II transcription. Reason: TBX20 synergistically activates cardiac Pol II target enhancers (Nppa, Gja5, Mef2c AHF, Nkx2-5) with partner TFs; also demonstrated for human TBX20 by luciferase and ChIP. Supporting Evidence: PMID:14550786 Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression PMID:15843409 Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers PMID:19762328 Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5 |
| GO:0048370 lateral mesoderm formation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from Xenopus tbx20 for lateral mesoderm formation. Reason: The Xenopus source (Stennard 2003) showed that ectopic overexpression of Tbx20a induced mesodermal and endodermal markers in Xenopus embryos. Gain-of-function induction of markers is not evidence that TBX20 normally participates in germ layer formation; no loss-of-function data support a role for TBX20 in endoderm or lateral mesoderm formation, and TBX20 expression begins in the cardiac crescent after gastrulation. Supporting Evidence: PMID:14550786 enforced expression of Tbx20a, but not Tbx20b, led to induction of mesodermal and endodermal lineage markers as well as cell migration |
| GO:0055008 cardiac muscle tissue morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer for cardiac muscle tissue morphogenesis. Reason: Tbx20 loss disrupts working myocardium formation and chamber morphogenesis; a general outcome term. Non-core. Supporting Evidence: PMID:15901664 dorsoventral patterning of the tube, formation of working myocardium, looping, and further differentiation and morphogenesis fail |
| GO:0055008 cardiac muscle tissue morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse for cardiac muscle tissue morphogenesis. Reason: Tbx20 loss disrupts working myocardium formation and chamber morphogenesis; a general outcome term. Non-core. Supporting Evidence: PMID:15901664 dorsoventral patterning of the tube, formation of working myocardium, looping, and further differentiation and morphogenesis fail |
| GO:0060045 positive regulation of cardiac muscle cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer (mouse IMP Singh 2005) for positive regulation of cardiac muscle cell proliferation. Reason: Tbx20 is necessary and sufficient for prenatal cardiomyocyte proliferation (mouse null and gain-of-function), and its overexpression promotes adult cardiomyocyte proliferation; Tbx20 activates Nmyc1. A reproducible output of TBX20 transcriptional regulation. Supporting Evidence: PMID:23751911 The T-box transcription factor Tbx20 is necessary and sufficient to promote prenatal cardiomyocyte proliferation |
| GO:0060045 positive regulation of cardiac muscle cell proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse for positive regulation of cardiac muscle cell proliferation. Reason: Tbx20 is necessary and sufficient for prenatal cardiomyocyte proliferation (mouse null and gain-of-function), and its overexpression promotes adult cardiomyocyte proliferation; Tbx20 activates Nmyc1. A reproducible output of TBX20 transcriptional regulation. Supporting Evidence: PMID:23751911 The T-box transcription factor Tbx20 is necessary and sufficient to promote prenatal cardiomyocyte proliferation |
| GO:0060413 atrial septum morphogenesis | IMP PMID:17668378 Mutations in cardiac T-box factor gene TBX20 are associated ... | ACCEPT | Summary: BHF-UCL IMP from Kirk et al. 2007 (TBX20 Q195X and I152M in families with CHD including ASD). Reason: TBX20 is the ASD4 disease gene: loss- and gain-of-function variants in the T-box segregate with secundum ASD in human families. Atrial septum morphogenesis is a well-supported human process for this gene. Supporting Evidence: PMID:17668378 associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis |
| GO:0060413 atrial septum morphogenesis | IMP PMID:18834961 T-box transcription factor TBX20 mutations in Chinese patien... | ACCEPT | Summary: BHF-UCL IMP from Liu et al. 2008 (TBX20 variants in Chinese CHD patients including ASD; abstract only). Reason: TBX20 is the ASD4 disease gene: loss- and gain-of-function variants in the T-box segregate with secundum ASD in human families. Atrial septum morphogenesis is a well-supported human process for this gene. Supporting Evidence: PMID:18834961 they probably contribute to the risk of atrial septal defect (ASD), total anomalous pulmonary venous connection (TAPVC) and tetralogy of Fallot (TOF) in a small subset of Chinese |
| GO:0060413 atrial septum morphogenesis | IMP PMID:19762328 A gain-of-function TBX20 mutation causes congenital atrial s... | ACCEPT | Summary: BHF-UCL IMP from Posch et al. 2010 (I121M gain-of-function variant segregating with ASDII). Reason: TBX20 is the ASD4 disease gene: loss- and gain-of-function variants in the T-box segregate with secundum ASD in human families. Atrial septum morphogenesis is a well-supported human process for this gene. Supporting Evidence: PMID:19762328 Four mutation carriers revealed cardiac phenotypes in terms of cribriform ASDII, large patent foramen ovale or cardiac valve defects PMID:19762328 Tbx20-I121M resulted in a significantly enhanced transcriptional activity, which was further increased in the presence of co-transcription factors GATA4/5 and NKX2-5 |
| GO:0060577 pulmonary vein morphogenesis | IMP PMID:18834961 T-box transcription factor TBX20 mutations in Chinese patien... | KEEP AS NON CORE | Summary: BHF-UCL IMP from Liu et al. 2008 linking a TBX20 variant to total anomalous pulmonary venous connection (abstract only). Reason: Single-patient association without functional data; the authors themselves say the variants "probably contribute". We defer to the curator but treat this as a weak, non-core developmental association. Supporting Evidence: PMID:18834961 they probably contribute to the risk of atrial septal defect (ASD), total anomalous pulmonary venous connection (TAPVC) and tetralogy of Fallot (TOF) in a small subset of Chinese |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog transfer (mouse IPI Stennard 2003) for Pol II-specific DNA-binding TF binding. Reason: TBX20 physically interacts with cardiac Pol II DNA-binding TFs NKX2-5, GATA4, GATA5 and TBX5, and synergizes with ISL1/GATA4; these interactions underlie cooperative activation of cardiac enhancers. Informative MF replacing generic protein binding. Supporting Evidence: PMID:14550786 Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression PMID:15634698 we show that TBX5 and TBX20 can physically interact and map the interaction domains |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse for Pol II-specific DNA-binding TF binding. Reason: TBX20 physically interacts with cardiac Pol II DNA-binding TFs NKX2-5, GATA4, GATA5 and TBX5, and synergizes with ISL1/GATA4; these interactions underlie cooperative activation of cardiac enhancers. Informative MF replacing generic protein binding. Supporting Evidence: PMID:14550786 Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression PMID:17668378 TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5 |
| GO:0090068 positive regulation of cell cycle process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer from rat IMP (Liu et al. 2016) for positive regulation of cell cycle process. Reason: TBX20 silencing caused G2/M arrest in H9c2 and HEK293 cells, consistent with the broader in vivo evidence that TBX20 promotes cardiomyocyte proliferation. Cell-line evidence; non-core. Supporting Evidence: PMID:27572266 Silencing of TBX20 in H9c2 and HEK293 cells significantly inhibited cell proliferation, induced cell apoptosis and led to G2/M cell cycle arrest PMID:23751911 The T-box transcription factor Tbx20 is necessary and sufficient to promote prenatal cardiomyocyte proliferation |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: IDA from Yin et al. 2017 HT-SELEX survey of human TF binding specificities (TBX20 data in supplementary tables). Reason: Sequence-specific double-stranded DNA binding is consistent with TBX20 T-box half-site binding in vitro and in vivo; we defer to the curator for the supplementary HT-SELEX data. Supporting Evidence: PMID:14550786 Isoforms with an intact T-box bound specifically to DNA sites resembling the consensus brachyury half site PMID:22328084 The TBX20 DNA-binding motif that we uncovered from our ChIP data ( 14 ) (consensus AGGTGNTGACAG) resembles known T-box DNA-binding motifs identified in vitro |
| GO:0046332 SMAD binding | ISS PMID:19661464 Tbx20 interacts with smads to confine tbx2 expression to the... | NEW | Summary: Proposed: SMAD1/SMAD5 binding, by similarity to mouse Tbx20 (Singh et al. 2009). Reason: Mouse Tbx20 (including DNA-binding-deficient mutants) binds Smad1 and Smad5 and sequesters them from Smad4, attenuating Bmp/Smad-dependent activation of the Tbx2 AVC enhancer; this is how Tbx20 confines Tbx2 to the AVC. The T-box domain is conserved in human TBX20. MGI annotates mouse Tbx20 to negative regulation of SMAD protein signal transduction (IDA, PMID:19661464), but no SMAD binding MF is annotated; the binding itself is the activity that executes the regulation. Supporting Evidence: PMID:19661464 both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4 |
| GO:0060392 negative regulation of SMAD protein signal transduction | ISS PMID:19661464 Tbx20 interacts with smads to confine tbx2 expression to the... | NEW | Summary: Proposed: negative regulation of SMAD signal transduction by SMAD1/5 sequestration, by similarity to mouse Tbx20 (MGI IDA). Reason: Mouse Tbx20 (including DNA-binding-deficient mutants) binds Smad1 and Smad5 and sequesters them from Smad4, attenuating Bmp/Smad-dependent activation of the Tbx2 AVC enhancer; this is how Tbx20 confines Tbx2 to the AVC. The T-box domain is conserved in human TBX20. MGI annotates mouse Tbx20 to negative regulation of SMAD protein signal transduction (IDA, PMID:19661464), but no SMAD binding MF is annotated; the binding itself is the activity that executes the regulation. TBX20 itself performs the regulatory step by binding the R-SMADs, so the participation test is met. Supporting Evidence: PMID:19661464 both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4 PMID:15843414 Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program |
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Download this section (compressed HTML)Q: How does TBX20 switch between activator and repressor output at a given target: isoform choice (Tbx20a C-terminal domains), partner cohort (NKX2-5/GATA4 vs repressive partners), or DNA-binding-independent SMAD sequestration?
Q: Which directly bound TBX20 targets in adult cardiomyocytes (ion channels, sarcomeric genes) account for the arrhythmia and cardiomyopathy seen after adult ablation, and are the same targets affected by human cardiomyopathy-associated variants?
Experiment: Map TBX20 interactomes (RIME/IP-MS) and isoform-specific ChIP-seq in human iPSC-derived cardiomyocytes, comparing activated vs repressed target loci, to define the partner cohorts that determine activator vs repressor output.
Experiment: Knock-in human ASD4 variants (I152M, I121M, Q195X) in iPSC-derived cardiomyocytes and measure target occupancy and expression (Nppa, Gja5, Tbx2) to test loss- vs gain-of-function mechanisms.
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