TBX5 is a T-box transcription factor of the TBX2/3/4/5 subfamily, expressed in the developing heart (atria, left ventricle, conduction system, epicardium) and forelimb. Its N-terminal T-box domain binds T-box elements (AGGTGTGA) in Pol II promoters and enhancers, and TBX5 mainly activates targets such as NPPA, GJA5/Cx40, FGF10, MYH6, ID2 and PITX2. It works cooperatively with partner cardiac transcription factors: it binds NKX2-5 (heterodimer on composite DNA elements), GATA4 and MEF2C, and interacts with SALL4 in limb and heart patterning. Coactivators TAZ/YAP1 and acetylation by KAT2A/KAT2B enhance its activity, and acetylation promotes nuclear retention. TBX5 shuttles between nucleus and cytoplasm, where the PDZ-LIM protein PDLIM7 (LMP4) tethers it to actin and represses it. In development TBX5 is required for forelimb bud initiation through direct activation of Fgf10, for atrial and ventricular septation, for posterior (inflow) heart growth, and in a dosage-sensitive way for patterning and maturation of the atrioventricular node and ventricular conduction system. In the adult atrium it maintains rhythm through a TBX5-PITX2 network. Heterozygous loss-of-function variants cause Holt-Oram syndrome (upper-limb radial-ray defects with atrial/ventricular septal defects and conduction block), and variants are associated with atrial fibrillation and dilated cardiomyopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | IBA GO_REF:0000033 | ACCEPT | Summary: PANTHER IBA: T-box TFs act at chromatin. Reason: TBX5 binds T-box elements in promoters/enhancers of target genes (e.g. Nppa) as a sequence-specific TF; chromatin is the correct site of action. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based assignment of chromatin localization for a sequence-specific DbTF. Reason: Consistent with direct promoter binding by TBX5. Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tbx5 of Pol II regulatory-region DNA binding. Reason: TBX5 binds T-box elements in Pol II promoters (Nppa, Fgf10, Cx40); supported by human structural data. Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA PMID:12490567 Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PANTHER IBA for Pol II cis-regulatory sequence-specific DNA binding. Reason: Inherited T-box DNA-binding function; supported by direct evidence for TBX5. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:26926761 Intermolecular Interactions of Cardiac Transcription Factors... | ACCEPT | Summary: Crystal structure of TBX5 and NKX2-5 DNA-binding domains bound to a 19-bp NPPA promoter element. Reason: Direct structural evidence for sequence-specific binding of a Pol II cis-regulatory element; core function. Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated IEA for Pol II cis-regulatory sequence-specific DNA binding. Reason: Consistent with experimental data. Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of Pol II cis-regulatory sequence-specific DNA binding from mouse. Reason: Consistent with experimental data on Nppa and Fgf10 promoters. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation PMID:12490567 Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: PANTHER IBA: Pol II-specific DNA-binding TF activity. Reason: Core function; T-box TFs are sequence-specific Pol II transcription factors, and TBX5 activates Nppa, Fgf10, Gja5 and MYH6. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:29174768 Acetylation of TBX5 by KAT2B and KAT2A regulates heart and l... | ACCEPT | Summary: KAT2A/KAT2B acetylation of TBX5 potentiates its transcriptional activity in reporter assays. Reason: Core function, directly assayed. Supporting Evidence: PMID:29174768 Acetylation potentiates its transcriptional activity and is required for nuclear retention |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass assignment of Pol II-specific DbTF activity. Reason: Correct core function. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of Pol II-specific transcription activator activity from mouse. Reason: TBX5 acts predominantly as an activator (Nppa, Gja5, Fgf10, MYH6, Pitx2). Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation PMID:12490567 Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of Pol II-specific transcription activator activity. Reason: Activator function is well supported. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation PMID:19204083 we report a physical interaction between TBX5 and MEF2C leading to a synergistic activation of the alpha-cardiac myosin heavy chain (MYH6) |
| GO:0001708 cell fate specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PANTHER IBA: cell fate specification for T-box factors. Reason: T-box family-level inference; for TBX5 the clearest specification role is the ventricular conduction system lineage (with NKX2-5 and ID2). TBX5 is not essential for forelimb-field identity, so this is a contributing, not core, role. Supporting Evidence: PMID:17604724 compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system |
| GO:0003163 sinoatrial node development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse of sinoatrial node development. Reason: Tbx5 null mice show severe hypoplasia of the posterior (sinoatrial/atrial) heart; a developmental role for a TF acting through target-gene regulation; non-core. Supporting Evidence: PMID:11572777 Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart |
| GO:0003163 sinoatrial node development | ISS PMID:11572777 A murine model of Holt-Oram syndrome defines roles of the T-... | KEEP AS NON CORE | Summary: ISS from mouse Tbx5 data (Bruneau 2001) for sinoatrial node development. Reason: Posterior heart hypoplasia in Tbx5 null mice supports a role in inflow/sinoatrial development; non-core subprocess of heart development. Supporting Evidence: PMID:11572777 Tbx5 deficiency in homozygous mice (Tbx5(del/del)) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart |
| GO:0003166 bundle of His development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of bundle of His development. Reason: Tbx5 is expressed in and required for patterning of the AV bundle and bundle branches. Supporting Evidence: PMID:15289437 Tbx5 haploinsufficiency caused patterning defects of both the left and right ventricular bundle branches PMID:15289437 We find that Tbx5 is expressed throughout the central conduction system, including the atrioventricular bundle and bundle branch conduction system |
| GO:0003166 bundle of His development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of bundle of His development. Reason: Supported by mouse haploinsufficiency phenotypes in the central conduction system. Supporting Evidence: PMID:15289437 Tbx5 haploinsufficiency caused patterning defects of both the left and right ventricular bundle branches |
| GO:0003167 atrioventricular bundle cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of atrioventricular bundle cell differentiation. Reason: Tbx5 with Nkx2-5 and Id2 is needed to specify ventricular conduction system cells. Supporting Evidence: PMID:17604724 compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system |
| GO:0003167 atrioventricular bundle cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of atrioventricular bundle cell differentiation. Reason: Supported by mouse compound haploinsufficiency data. Supporting Evidence: PMID:17604724 compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system |
| GO:0003218 cardiac left ventricle formation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PANTHER IBA: cardiac left ventricle formation. Reason: In birds and mammals Tbx5 marks left ventricle precursors and its gradient sets ventricular septation; a genuine but subsidiary developmental role. Supporting Evidence: PMID:19727199 in birds and mammals, Tbx5 is restricted to left ventricle precursors PMID:19727199 loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation |
| GO:0003218 cardiac left ventricle formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of cardiac left ventricle formation. Reason: As above. Supporting Evidence: PMID:19727199 in birds and mammals, Tbx5 is restricted to left ventricle precursors |
| GO:0003218 cardiac left ventricle formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of cardiac left ventricle formation. Reason: As above. Supporting Evidence: PMID:19727199 in birds and mammals, Tbx5 is restricted to left ventricle precursors |
| GO:0003281 ventricular septum development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of ventricular septum development. Reason: Ventricular loss of Tbx5 in mouse produces a single unseptated ventricle; VSDs occur in Holt-Oram syndrome. Supporting Evidence: PMID:19727199 loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation |
| GO:0003281 ventricular septum development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer of ventricular septum development. Reason: As above. Supporting Evidence: PMID:19727199 loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation |
| GO:0003677 DNA binding | IDA PMID:16332960 A WW domain protein TAZ is a critical coactivator for TBX5, ... | MODIFY | Summary: TAZ-coactivation study annotated generic DNA binding. Reason: DNA binding is correct but uninformative; TBX5 binds T-box elements in Pol II cis-regulatory regions (structure and promoter-binding data). Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of generic DNA binding. Reason: Replace with the specific Pol II cis-regulatory sequence-specific binding term already supported experimentally. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | ACCEPT | Summary: TBX5 binds the Nppa promoter and activates it synergistically with NKX2-5. Reason: Direct evidence of DNA-binding TF activity; GO:0000981 is the more specific Pol II term, also present. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:12499378 Functional analysis of TBX5 missense mutations associated wi... | ACCEPT | Summary: EMSA and reporter assays of wild-type and HOS mutant TBX5. Reason: DNA binding and transcriptional activation assayed directly. Supporting Evidence: PMID:12499378 Mutations G80R, R237Q, and R237W represent a group of mutations that dramatically reduce DNA-binding activity of TBX5, leading to reduced transcription activation by TBX5 PMID:12499378 The synthetic TBX5-binding site was generated by annealing double-stranded oligonucleotides |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:16332960 A WW domain protein TAZ is a critical coactivator for TBX5, ... | ACCEPT | Summary: Reporter assays showing TBX5-dependent promoter activation, enhanced by TAZ. Reason: Consistent with the TF activity of TBX5; curator saw full text. Supporting Evidence: PMID:16332960 TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA for DNA-binding TF activity. Reason: Correct, if general. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0003700 DNA-binding transcription factor activity | IMP PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | ACCEPT | Summary: G80R HOS mutant fails to activate Nppa. Reason: Loss-of-function mutant evidence for TF activity. Supporting Evidence: PMID:11431700 A G80R mutation of Tbx5, which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not activate Nppa or show synergistic activation |
| GO:0005515 protein binding | IPI PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | MODIFY | Summary: Y2H/co-IP/GST pull-down: TBX5 binds NKX2-5 via its N-terminus and T-box. Reason: Generic protein binding; the partner is a Pol II DNA-binding TF, and the interaction underlies synergistic Nppa activation. Matches the NKX2-5 review in this repository, which uses GO:0061629 for the same interaction. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:11431700 the N-terminal domain and N-terminal part of the T-box of Tbx5 and the homeodomain of Nkx2-5 were necessary for their interaction PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0005515 protein binding | IPI PMID:12499378 Functional analysis of TBX5 missense mutations associated wi... | MODIFY | Summary: HOS missense mutations reduce TBX5-NKX2-5 interaction and synergy. Reason: Replace generic protein binding with DNA-binding TF binding (consistent with NKX2-5 review). Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:12499378 All seven missense mutations greatly reduced the interaction of TBX5 with NKX2.5 in vivo and in vitro. |
| GO:0005515 protein binding | IPI PMID:12845333 GATA4 mutations cause human congenital heart defects and rev... | MODIFY | Summary: GATA4 paper; IPI with mouse Nkx2-5 (P42582). Reason: Partner is a DNA-binding TF; use TF binding. The cached abstract focuses on GATA4, but the curator saw the full text, so the interaction with Nkx2-5 is not disputed. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:12845333 interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects |
| GO:0005515 protein binding | IPI PMID:12845333 GATA4 mutations cause human congenital heart defects and rev... | MODIFY | Summary: TBX5 physically interacts with GATA4; disrupted by GATA4 G296S and TBX5 HOS mutations. Reason: Partner is a DNA-binding TF; replace generic protein binding. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:12845333 the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5 PMID:12845333 interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects |
| GO:0005515 protein binding | IPI PMID:12845333 GATA4 mutations cause human congenital heart defects and rev... | MODIFY | Summary: TBX5 interacts with mouse Gata4. Reason: Replace generic protein binding with DNA-binding TF binding. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:12845333 the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5 |
| GO:0005515 protein binding | IPI PMID:16332960 A WW domain protein TAZ is a critical coactivator for TBX5, ... | MODIFY | Summary: TBX5 directly binds the WW-domain coactivator TAZ (WWTR1). Reason: TAZ is a transcriptional coactivator, not a DNA-binding TF; transcription coactivator binding is the informative term. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:16332960 TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF |
| GO:0005515 protein binding | IPI PMID:23245941 Ξ²-Catenin-driven cancers require a YAP1 transcriptional comp... | MODIFY | Summary: TBX5 co-immunoprecipitates with YAP1 and beta-catenin in cancer cells. Reason: YAP1 is a transcriptional coactivator; replace generic protein binding with coactivator binding. Context is cancer cell lines but TAZ/YAP coactivation of TBX5 is also seen in the TAZ study. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:23245941 we isolated TBX5-specific immune complexes from 293T or DLD1 cells and found that TBX5 binds to both Ξ²-catenin and YAP1 PMID:16332960 YAP, a TAZ-related protein with conserved functional domains, also stimulates TBX5-dependent transcription |
| GO:0005515 protein binding | IPI PMID:24000169 GATA4 loss-of-function mutations underlie familial tetralogy... | MODIFY | Summary: GATA4 N285S abolishes GATA4-TBX5 interaction. Reason: Partner is a DNA-binding TF. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:24000169 the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5 |
| GO:0005515 protein binding | IPI PMID:26926761 Intermolecular Interactions of Cardiac Transcription Factors... | MODIFY | Summary: Crystal structure of TBX5-NKX2-5 heterodimer on DNA. Reason: Replace generic protein binding with DNA-binding TF binding, consistent with the NKX2-5 review. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:26926761 The ternary complex structure of NKX2.5 and TBX5 with the target DNA shows physical interactions between the two proteins through Lys158 (NKX2.5), Asp140 (TBX5), and Pro142 (TBX5) |
| GO:0005515 protein binding | IPI PMID:29174768 Acetylation of TBX5 by KAT2B and KAT2A regulates heart and l... | MODIFY | Summary: KAT2A associates with and acetylates TBX5. Reason: TBX5 is the acetylation substrate; histone acetyltransferase binding describes the interaction more informatively than protein binding. Proposed replacements: histone acetyltransferase binding Supporting Evidence: PMID:29174768 histone acetyltransferases KAT2A and KAT2B associate with TBX5 and acetylate it at Lys339 |
| GO:0005515 protein binding | IPI PMID:29174768 Acetylation of TBX5 by KAT2B and KAT2A regulates heart and l... | MODIFY | Summary: KAT2B associates with and acetylates TBX5. Reason: As for KAT2A. Proposed replacements: histone acetyltransferase binding Supporting Evidence: PMID:29174768 histone acetyltransferases KAT2A and KAT2B associate with TBX5 and acetylate it at Lys339 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary Y2H interaction with ZMYND10. Reason: Single high-throughput Y2H hit with no functional context in heart or limb; generic protein binding is uninformative and no specific function can be inferred. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary Y2H interaction with BAIAP2 isoform 6. Reason: Single high-throughput Y2H hit with no biological context; generic protein binding is uninformative. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: PANTHER IBA: active in nucleus. Reason: TBX5 is a nuclear TF with two cooperating NLSs. Supporting Evidence: PMID:14519429 We identified two distinct nuclear localization signals in TBX5, one monopartite and one bipartite |
| GO:0005634 nucleus | IDA PMID:12237100 Induction of apoptosis and inhibition of cell growth by deve... | ACCEPT | Summary: Nuclear localization of ectopically expressed TBX5 in growth-inhibition study. Reason: Nucleus is the site of action; consistent with other evidence. Supporting Evidence: PMID:14519429 We identified two distinct nuclear localization signals in TBX5, one monopartite and one bipartite |
| GO:0005634 nucleus | IDA PMID:12499378 Functional analysis of TBX5 missense mutations associated wi... | ACCEPT | Summary: Wild-type TBX5 is fully nuclear in immunofluorescence. Reason: Direct evidence. Supporting Evidence: PMID:12499378 Immunofluorescent staining showed that wild type TBX5 was localized completely into the nucleus, but mutants were localized in both nucleus and cytoplasm. |
| GO:0005634 nucleus | IDA PMID:14519429 TBX5 nuclear localization is mediated by dual cooperative in... | ACCEPT | Summary: Mapping of two cooperative NLSs in TBX5. Reason: Direct evidence. Supporting Evidence: PMID:14519429 We identified two distinct nuclear localization signals in TBX5, one monopartite and one bipartite |
| GO:0005634 nucleus | IDA PMID:29174768 Acetylation of TBX5 by KAT2B and KAT2A regulates heart and l... | ACCEPT | Summary: Acetylation-dependent nuclear retention of TBX5. Reason: Direct evidence. Supporting Evidence: PMID:29174768 Acetylation potentiates its transcriptional activity and is required for nuclear retention |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA: nucleus. Reason: Correct. Supporting Evidence: PMID:14519429 We identified two distinct nuclear localization signals in TBX5, one monopartite and one bipartite |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2032794 | ACCEPT | Summary: Reactome: TAZ-TBX5-PCAF complex in nucleoplasm. Reason: Consistent with nuclear TF and coactivator complex. Supporting Evidence: PMID:16332960 TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer: part of transcription regulator complex. Reason: TBX5 forms DNA-bound complexes with NKX2-5 and coactivator complexes with TAZ/YAP; reasonable but a general descriptor. Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA PMID:16332960 TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF |
| GO:0005737 cytoplasm | IDA PMID:14519429 TBX5 nuclear localization is mediated by dual cooperative in... | KEEP AS NON CORE | Summary: NLS-mutant analysis found TBX5 also in cytoplasm; nuclear localization not uniform in organogenesis. Reason: TBX5 shuttles; cytoplasmic pools are regulatory (PDLIM7/LMP4 tethering), not a site of core function. Supporting Evidence: PMID:14519429 Current analyses suggest that TBX5 nuclear localization is not uniform during organogenesis PMID:16880269 In the presence of LMP4, Tbx5 shuttles dynamically between the nucleus and cytoplasm and, in a complex with LMP4, localizes to actin filaments |
| GO:0005737 cytoplasm | IDA PMID:29174768 Acetylation of TBX5 by KAT2B and KAT2A regulates heart and l... | KEEP AS NON CORE | Summary: Unacetylated TBX5 is found in the cytoplasm; acetylation promotes nuclear retention. Reason: Regulatory nucleocytoplasmic shuttling; non-core location. Supporting Evidence: PMID:29174768 Acetylation potentiates its transcriptional activity and is required for nuclear retention |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping: cytoplasm. Reason: Shuttling is documented; non-core. Supporting Evidence: PMID:16880269 In the presence of LMP4, Tbx5 shuttles dynamically between the nucleus and cytoplasm and, in a complex with LMP4, localizes to actin filaments |
| GO:0005737 cytoplasm | TAS PMID:20299672 Epicardial-myocardial signaling directing coronary vasculoge... | KEEP AS NON CORE | Summary: TAS from a review of epicardial-myocardial growth-factor signalling. Reason: The cached text of this review does not mention TBX5, but cytoplasmic TBX5 is independently documented (LMP4-mediated shuttling); non-core. Supporting Evidence: PMID:16880269 In the presence of LMP4, Tbx5 shuttles dynamically between the nucleus and cytoplasm and, in a complex with LMP4, localizes to actin filaments |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO: regulation of DNA-templated transcription. Reason: Correct general process for a T-box TF; more specific Pol II terms also present. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: PANTHER IBA: regulation of transcription by RNA polymerase II. Reason: Core process for the T-box TF family including TBX5. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0007267 cell-cell signaling | IDA PMID:11161571 TBX5 transcription factor regulates cell proliferation durin... | MARK AS OVER ANNOTATED | Summary: TBX5 overexpression inhibits proliferation of neighbouring non-transgenic cells. Reason: A non-cell-autonomous overexpression effect implies an unidentified secreted downstream signal; TBX5 itself is a nuclear TF and does not perform cell-cell signalling. Supporting Evidence: PMID:11161571 Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo |
| GO:0007267 cell-cell signaling | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS: acts upstream of cell-cell signaling. Reason: Indirect downstream consequence of transcriptional regulation (e.g. Fgf10, Gja5 expression); not informative for a TF. Supporting Evidence: PMID:12490567 Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation |
| GO:0007389 pattern specification process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PANTHER IBA: pattern specification process. Reason: TBX5 patterns the ventricles and conduction system and anterior forelimb (with SALL4); family-level, non-core. Supporting Evidence: PMID:19727199 loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation PMID:16380715 Tbx5 and Sall4 interact both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart |
| GO:0007507 heart development | IDA PMID:15138308 A role for Tbx5 in proepicardial cell migration during cardi... | ACCEPT | Summary: TBX5 expression in epicardium/coronary vasculature and role in proepicardial migration. Reason: Heart development is a core biological process for TBX5; the module annoton process. Supporting Evidence: PMID:15138308 TBX5 transcription factor is expressed not only in the myocardium, but also throughout the embryonic epicardium and coronary vasculature PMID:15138308 TBX5 overexpression as well as antisense-mediated knockdown of chick Tbx5 produce a cell-autonomous defect in the PEO that prevents proepicardial cell migration |
| GO:0007507 heart development | IMP PMID:16183809 TBX5 genetic testing validates strict clinical criteria for ... | ACCEPT | Summary: TBX5 mutations cause Holt-Oram syndrome with congenital heart disease. Reason: Human genetic evidence for a role in heart development. Supporting Evidence: PMID:16183809 Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene |
| GO:0007507 heart development | IMP PMID:25963046 A novel TBX5 loss-of-function mutation associated with spora... | ACCEPT | Summary: TBX5 A143T variant in DCM reduces ANF activation and GATA4 synergy. Reason: Supports cardiac developmental/regulatory function; heart development is core (well supported by stronger data). Supporting Evidence: PMID:25963046 the A143T mutation abolished the synergistic activation of the ANF promoter between TBX5 and GATA binding protein 4 (GATA4) |
| GO:0007507 heart development | IMP PMID:8988164 Holt-Oram syndrome is caused by mutations in TBX5, a member ... | ACCEPT | Summary: HOS truncating mutations; TBX5 expressed in embryonic heart and limb. Reason: Human genetic evidence for heart development. Supporting Evidence: PMID:8988164 Each of the mutations introduces a premature stop codon in the TBX5 gene product PMID:8988164 reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development |
| GO:0007507 heart development | IMP PMID:8988165 Mutations in human TBX5 [corrected] cause limb and cardiac m... | ACCEPT | Summary: TBX5 mutations cause HOS limb and cardiac malformations. Reason: Core process. Supporting Evidence: PMID:8988165 We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome |
| GO:0007507 heart development | IMP PMID:8988165 Mutations in human TBX5 [corrected] cause limb and cardiac m... | ACCEPT | Summary: As above, involved_in heart development. Reason: Core process. Supporting Evidence: PMID:8988165 We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:11161571 TBX5 transcription factor regulates cell proliferation durin... | KEEP AS NON CORE | Summary: TBX5 overexpression suppresses cardiomyocyte proliferation in chick heart and cultured cells. Reason: Overexpression-based; plausible contribution to cardiac growth control but not a core function. Supporting Evidence: PMID:11161571 PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:12237100 Induction of apoptosis and inhibition of cell growth by deve... | KEEP AS NON CORE | Summary: Ectopic TBX5 inhibits colony formation and growth of cultured cell lines. Reason: Overexpression in non-cardiac cell lines; growth suppression is consistent with the antiproliferative effect seen in heart but is not a core physiological function of TBX5. Supporting Evidence: PMID:12237100 ectopic expression of TBX5 inhibited colony formation, induced apoptosis, and decreased the growth rate of cells |
| GO:0010719 negative regulation of epithelial to mesenchymal transition | TAS PMID:20299672 Epicardial-myocardial signaling directing coronary vasculoge... | UNDECIDED | Summary: TAS from a review of coronary vasculogenesis signalling. Reason: The cached review text does not mention TBX5; the primary study (PMID:15138308) only shows TBX5 downregulation before EMT and dosage-sensitive proepicardial migration, not negative regulation of EMT. Cannot verify the curator source. Supporting Evidence: PMID:15138308 Thus, both increasing and decreasing Tbx5 dosage impairs development of the proepicardium |
| GO:0030326 embryonic limb morphogenesis | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA: embryonic limb morphogenesis. Reason: TBX5 is required for forelimb bud initiation and outgrowth; core. Supporting Evidence: PMID:12490567 mouse embryos lacking Tbx5 do not form forelimb buds PMID:12736217 we demonstrate that this gene is also required at early limb bud stages for forelimb bud development |
| GO:0030326 embryonic limb morphogenesis | IMP PMID:8988164 Holt-Oram syndrome is caused by mutations in TBX5, a member ... | ACCEPT | Summary: HOS mutations cause upper-limb malformation. Reason: Core process (forelimb). Supporting Evidence: PMID:8988164 reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development |
| GO:0030336 negative regulation of cell migration | IDA PMID:15138308 A role for Tbx5 in proepicardial cell migration during cardi... | KEEP AS NON CORE | Summary: TBX5 overexpression blocks proepicardial cell migration. Reason: Both gain and loss of Tbx5 impair proepicardial migration, so a simple negative-regulation reading is uncertain; dosage-dependent role in proepicardium development, non-core. Supporting Evidence: PMID:15138308 TBX5 overexpression as well as antisense-mediated knockdown of chick Tbx5 produce a cell-autonomous defect in the PEO that prevents proepicardial cell migration PMID:15138308 Thus, both increasing and decreasing Tbx5 dosage impairs development of the proepicardium |
| GO:0032991 protein-containing complex | IDA PMID:26926761 Intermolecular Interactions of Cardiac Transcription Factors... | MODIFY | Summary: TBX5-NKX2-5-DNA ternary complex in crystal structure. Reason: Generic complex term; protein-DNA complex (also annotated) describes the observed TBX5-NKX2-5-DNA assembly. Proposed replacements: protein-DNA complex Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA |
| GO:0032993 protein-DNA complex | IDA PMID:26926761 Intermolecular Interactions of Cardiac Transcription Factors... | KEEP AS NON CORE | Summary: TBX5-NKX2-5 DNA-binding domains crystallized on target DNA. Reason: Correct for the crystallized complex; a structural rather than physiological complex descriptor. Supporting Evidence: PMID:26926761 Here we report a crystal structure of human NKX2.5 and TBX5 DNA binding domains in a complex with a 19 bp target DNA |
| GO:0035115 embryonic forelimb morphogenesis | IMP PMID:16183809 TBX5 genetic testing validates strict clinical criteria for ... | ACCEPT | Summary: Strict HOS criteria require preaxial radial ray malformation. Reason: Human genetic evidence for forelimb morphogenesis. Supporting Evidence: PMID:16183809 validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation |
| GO:0035136 forelimb morphogenesis | IMP PMID:8988164 Holt-Oram syndrome is caused by mutations in TBX5, a member ... | ACCEPT | Summary: HOS limb malformation from TBX5 truncations. Reason: Core process. Supporting Evidence: PMID:8988164 reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development |
| GO:0035136 forelimb morphogenesis | IMP PMID:8988165 Mutations in human TBX5 [corrected] cause limb and cardiac m... | ACCEPT | Summary: HOS limb malformation from TBX5 mutations. Reason: Core process. Supporting Evidence: PMID:8988165 We conclude that TBX5 is critical for limb and heart development and suggest that haploinsufficiency of TBX5 causes Holt-Oram syndrome |
| GO:0043565 sequence-specific DNA binding | IDA PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | ACCEPT | Summary: TBX5 binds the Nppa promoter. Reason: Direct sequence-specific binding. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0043565 sequence-specific DNA binding | IDA PMID:12499378 Functional analysis of TBX5 missense mutations associated wi... | ACCEPT | Summary: EMSA with a synthetic T-box binding site. Reason: Direct sequence-specific DNA binding. Supporting Evidence: PMID:12499378 The synthetic TBX5-binding site was generated by annealing double-stranded oligonucleotides |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | ACCEPT | Summary: Synergistic activation of Nppa promoter with NKX2-5. Reason: Reporter evidence for activation. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:12499378 Functional analysis of TBX5 missense mutations associated wi... | ACCEPT | Summary: Reporter assays: TBX5 activates and synergizes with NKX2.5. Reason: Direct evidence. Supporting Evidence: PMID:12499378 Mutations G80R, R237Q, and R237W represent a group of mutations that dramatically reduce DNA-binding activity of TBX5, leading to reduced transcription activation by TBX5 |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:12845333 GATA4 mutations cause human congenital heart defects and rev... | ACCEPT | Summary: GATA4-TBX5 synergistic activation. Reason: Reporter-based activation; curator saw full text. Supporting Evidence: PMID:12845333 the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5 |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:16332960 A WW domain protein TAZ is a critical coactivator for TBX5, ... | ACCEPT | Summary: TAZ stimulates TBX5-dependent promoters. Reason: Direct reporter evidence. Supporting Evidence: PMID:16332960 TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:27035640 TBX5 loss-of-function mutation contributes to atrial fibrill... | ACCEPT | Summary: AF-associated P132S reduces TBX5 transcriptional activity. Reason: Wild-type activation measured as comparator. Supporting Evidence: PMID:27035640 Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO: positive regulation of DNA-templated transcription. Reason: Correct. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:29174768 Acetylation of TBX5 by KAT2B and KAT2A regulates heart and l... | ACCEPT | Summary: Acetylation potentiates TBX5 transcriptional activity. Reason: Direct reporter evidence. Supporting Evidence: PMID:29174768 Acetylation potentiates its transcriptional activity and is required for nuclear retention |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara: positive regulation of transcription by Pol II. Reason: Correct core process. Supporting Evidence: PMID:12490567 Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | ACCEPT | Summary: G80R mutant fails to activate Nppa. Reason: Direct mutational evidence. Supporting Evidence: PMID:11431700 A G80R mutation of Tbx5, which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not activate Nppa or show synergistic activation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ISS: positive regulation of transcription by Pol II. Reason: Correct. Supporting Evidence: PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0051891 positive regulation of cardioblast differentiation | IDA PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | KEEP AS NON CORE | Summary: Tbx5-overexpressing P19CL6 cells beat earlier and express more cardiac genes. Reason: Overexpression in an embryonal carcinoma model; supports a promoting role in cardiomyocyte differentiation, but cardioblast-stage specificity is not established. Supporting Evidence: PMID:11431700 P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells |
| GO:0055007 cardiac muscle cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of cardiac muscle cell differentiation. Reason: Supported by P19CL6 and MEF2C/MYH6 data; non-core. Supporting Evidence: PMID:11431700 P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells PMID:19204083 we report a physical interaction between TBX5 and MEF2C leading to a synergistic activation of the alpha-cardiac myosin heavy chain (MYH6) |
| GO:0060039 pericardium development | IDA PMID:15138308 A role for Tbx5 in proepicardial cell migration during cardi... | KEEP AS NON CORE | Summary: TBX5 expressed in and required for proepicardial organ development. Reason: Proepicardium gives rise to the epicardium (visceral pericardium); dosage-sensitive role, non-core. Supporting Evidence: PMID:15138308 Thus, both increasing and decreasing Tbx5 dosage impairs development of the proepicardium |
| GO:0060044 negative regulation of cardiac muscle cell proliferation | IDA PMID:11161571 TBX5 transcription factor regulates cell proliferation durin... | KEEP AS NON CORE | Summary: TBX5 overexpression suppresses cardiomyocyte proliferation in chick heart. Reason: Overexpression evidence; non-core. Supporting Evidence: PMID:11161571 PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo |
| GO:0060371 regulation of atrial cardiac muscle cell membrane depolarization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: adult Tbx5 loss causes atrial depolarization abnormalities. Reason: Adult Tbx5 maintains atrial rhythm through transcription of membrane effector genes (via PITX2 network); acts upstream, non-core. Supporting Evidence: PMID:27582060 Atrial cardiomyocytes from the Tbx5-mutant mice exhibited action potential abnormalities, including spontaneous depolarizations PMID:27582060 TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2 |
| GO:0060928 atrioventricular node cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara: atrioventricular node cell development. Reason: AV node maturation fails in Tbx5 haploinsufficient mice. Supporting Evidence: PMID:15289437 Electrophysiologic testing of Tbx5(del/+) mice suggested a specific atrioventricular node maturation failure |
| GO:0060928 atrioventricular node cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS: atrioventricular node cell development. Reason: As above. Supporting Evidence: PMID:15289437 Electrophysiologic testing of Tbx5(del/+) mice suggested a specific atrioventricular node maturation failure |
| GO:0060929 atrioventricular node cell fate commitment | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara: atrioventricular node cell fate commitment. Reason: Conduction-system specification requires Tbx5 with Nkx2-5/Id2; non-core. Supporting Evidence: PMID:17604724 compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system |
| GO:0060929 atrioventricular node cell fate commitment | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS: atrioventricular node cell fate commitment. Reason: As above. Supporting Evidence: PMID:17604724 compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system |
| GO:0060980 cell migration involved in coronary vasculogenesis | TAS PMID:20299672 Epicardial-myocardial signaling directing coronary vasculoge... | KEEP AS NON CORE | Summary: TAS from a review of coronary vasculogenesis. Reason: Cached review text does not mention TBX5, but the primary study shows Tbx5 dosage controls proepicardial cell migration into epicardium and coronary vasculature; non-core. Supporting Evidence: PMID:15138308 TBX5 overexpression as well as antisense-mediated knockdown of chick Tbx5 produce a cell-autonomous defect in the PEO that prevents proepicardial cell migration |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:11431700 Tbx5 associates with Nkx2-5 and synergistically promotes car... | ACCEPT | Summary: TBX5 binds NKX2-5 (Y2H, co-IP, pull-down). Reason: Core function: cooperative partnership with NKX2-5 on cardiac promoters; consistent with NKX2-5 review. Supporting Evidence: PMID:11431700 the N-terminal domain and N-terminal part of the T-box of Tbx5 and the homeodomain of Nkx2-5 were necessary for their interaction PMID:11431700 Tbx5 and Nkx2-5 directly bound to the promoter of the gene for cardiac-specific natriuretic peptide precursor type A (Nppa) in tandem, and both transcription factors showed synergistic activation |
| GO:0086054 bundle of His cell to Purkinje myocyte communication by electrical coupling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS: acts upstream of His-Purkinje electrical coupling. Reason: Tbx5 transcriptionally activates Gja5/Cx40; the coupling itself is performed by gap junctions; acts-upstream qualifier is appropriate. Supporting Evidence: PMID:11572777 Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription |
| GO:1901846 positive regulation of cell communication by electrical coupling involved in cardiac conduction | TAS PMID:15289437 The T-Box transcription factor Tbx5 is required for the patt... | KEEP AS NON CORE | Summary: Tbx5 haploinsufficiency conduction defects; Cx40 is a Tbx5 target. Reason: Indirect, via Cx40 transcription; acts upstream. Supporting Evidence: PMID:15289437 Deficiencies in the gap junction protein gene connexin 40 (Cx40), a downstream target of Tbx5, did not account for morphologic conduction system defects PMID:11572777 Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription |
| GO:1903598 positive regulation of gap junction assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara: positive regulation of gap junction assembly. Reason: TBX5 activates connexin gene transcription; it does not regulate the assembly of gap junctions per se. Supporting Evidence: PMID:11572777 Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription |
| GO:1903598 positive regulation of gap junction assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS: positive regulation of gap junction assembly. Reason: As above; indirect transcriptional effect on Cx40 levels. Supporting Evidence: PMID:11572777 Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription |
| GO:1903781 positive regulation of cardiac conduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS: acts upstream of positive regulation of cardiac conduction. Reason: Tbx5 controls conduction-system development and atrial rhythm gene expression; acts upstream, non-core. Supporting Evidence: PMID:15289437 Tbx5 haploinsufficiency caused patterning defects of both the left and right ventricular bundle branches PMID:27582060 TBX5 directly activated PITX2, and TBX5 and PITX2 antagonistically regulated membrane effector genes Scn5a, Gja1, Ryr2, Dsp, and Atp2a2 |
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Download this section (compressed HTML)Q: Should TBX5 carry GO:0060174 limb bud formation (or a forelimb-specific child), given direct Fgf10 activation and absence of forelimb buds in Tbx5 null mice, and why is mouse Tbx5 not annotated to it?
Q: Does cytoplasmic TBX5 (PDLIM7/LMP4-bound, actin-associated) have any function of its own, or is it purely a regulatory sequestration pool?
Q: Which TBX5 targets mediate its non-cell-autonomous inhibition of cardiomyocyte proliferation in overexpression studies, and is this physiological?
Experiment: CUT&RUN for TBX5, NKX2-5 and GATA4 in isogenic TBX5 wild-type, heterozygous-null and missense-knock-in human iPSC-derived atrial and conduction-like cardiomyocytes, combined with ATAC-seq and RNA-seq.
Hypothesis: HOS missense variants differ in whether they impair DNA binding or partner-TF cooperativity at specific atrial and conduction-system enhancers.
Type: genome-wide DNA-binding and transcriptomic profiling
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