TBX20

TBX20 (gene) is a member of the T-box family that encodes the transcription factor TBX20. Studies in mouse, human and fruitfly have shown that this gene is essential for early heart development,[5][6][7][8] adult heart function[9] and yolk sac vasculature remodeling[7] and has been associated with congenital heart diseases.[10][11][12] Tbx20 was also shown to be required for migration of hindbrain motor neurons and in facial neurons was proposed to be a positive regulator of the non-canonical Wnt signaling pathway.

TBX20
Identifiers
Aliases	TBX20, T-box 20, ASD4, T-box transcription factor 20
External IDs	OMIM: 606061 MGI: 1888496 HomoloGene: 32476 GeneCards: TBX20
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p14.2 Start 35,202,430 bp[1] End 35,254,100 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 A4 Start 24,718,138 bp[2] End 24,774,303 bp[2]
Gene ontology Molecular function • DNA binding • GO:0001105 transcription coactivator activity • RNA polymerase II regulatory region sequence-specific DNA binding • RNA polymerase II transcription factor binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • RNA polymerase II activating transcription factor binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • cytoplasm • cell nucleus Biological process • cardiac septum development • pulmonary vein morphogenesis • muscle contraction • regulation of transcription, DNA-templated • negative regulation of SMAD protein complex assembly • aortic valve morphogenesis • outflow tract morphogenesis • cardiac muscle tissue morphogenesis • neuron migration • negative regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • blood circulation • transcription, DNA-templated • pulmonary valve formation • embryonic heart tube development • outflow tract septum morphogenesis • endocardial cushion morphogenesis • heart looping • endocardial cushion formation • atrial septum morphogenesis • multicellular organism development • positive regulation of transcription, DNA-templated • lateral mesoderm formation • positive regulation of cardiac muscle cell proliferation • visceral motor neuron differentiation • embryonic heart tube morphogenesis • aortic valve development • pericardium morphogenesis • branching involved in blood vessel morphogenesis • cardiac chamber formation • endoderm formation • cellular proliferation • negative regulation of transcription, DNA-templated • dorsal/ventral pattern formation • cardiac right ventricle morphogenesis • foramen ovale closure • tricuspid valve development • positive regulation of transcription from RNA polymerase II promoter • embryonic heart tube elongation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	57057	57246
Ensembl	ENSG00000164532	ENSMUSG00000031965
UniProt	Q9UMR3	Q9ES03
RefSeq (mRNA)	NM_020417 NM_001077653 NM_001166220	NM_001205085 NM_020496 NM_194263
RefSeq (protein)	NP_001071121 NP_001159692	NP_001192014 NP_065242 NP_919239
Location (UCSC)	Chr 7: 35.2 – 35.25 Mb	Chr 9: 24.72 – 24.77 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Tbx20 is a transcription factor that is essential for proper heart development in a growing fetus. Any mutations in this gene can result in various forms of congenital heart disease. One of the more serious examples is the presence of a septal defect. The interatrial septum is a piece of tissue that separates the left and right atria of the heart, which contain oxygenated and deoxygenated blood, respectively. In Tbx20 mutants, this divider does not form and results in deoxygenated blood flowing into the left atrium then left ventricle, which ships the blood to the organs and muscles. Since deoxygenated blood should not be delivered to the tissues, the result is cyanosis, or a bluish skin discoloration stemming from low oxygen concentration. Proper function of Tbx20 is essential because it controls other genes that regulate cardiomyocyte proliferation, such as Tbx2 and N-myc1. Cardiomyocytes are the basis for the correct architectural scheme of the heart, and if defects arise in these structures, proper heart development is likely unattainable.[13]

Embryonic heart functions

Tbx20 knockout mouse embryos die at around or before E10.5 with hypoplastic hearts.[5][6][7][8]

This gene has been implicated in coordinating cardiac proliferation, regional specification[5] and formation of the cardiac chamber[6][7][8] Congenital heart diseases involving TBX20 include defects in septation, chamber growth and valvulogenesis[10][11] and increased Tbx20 expression was shown to cause congenital atrial septal defects, patent foramen ovale and cardiac valve defects.[12]

Adult heart functions

In the fruitfly, knock-down of nmr (neuromancer), Drosophila's Tbx20 homolog gene, led to slower heart rate, arrythmias and abnormal myofibrillar architecture.[9] Heterozygous Tbx20 knockout adult mice displayed left ventricle dilation, decreased wall thickness and contractile abnormalities.[7] Homozygous conditional cardiomyocyte Tbx20 knockout adult mice died within 15 days after knockout induction. Mice hearts presented with dilated cardiomyopathy and contraction-related dysfunctions such as abnormal atrioventricular conduction, slower heart rate, altered ventricular depolarization/repolarization and arrhythmias.[14]

Known co-factors

Transcription factors GATA4 and NKX2-5 have been shown to physically interact with TBX20 and enhance gene expression.[7]

Known downstream gene targets

Tbx2 was shown to be directly repressed by Tbx20 in the myocardium.[5][7] Analysis of data from genome-wide chromatin immunoprecipitation against TBX20 tagged with green fluorescent protein in adult (6–8 weeks) mouse whole heart, coupled with analysis of genes differentially expressed upon loss of Tbx20, identified hundreds of putative TBX20 direct targets.[14][15]

References

1. GRCh38: Ensembl release 89: ENSG00000164532 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031965 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Cai CL, Zhou W, Yang L, Bu L, Qyang Y, Zhang X, Li X, Rosenfeld MG, Chen J, Evans S (May 2005). "T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis". Development. 132 (10): 2475–87. doi:10.1242/dev.01832. PMC 5576439. PMID 15843407.
6. Singh MK, Christoffels VM, Dias JM, Trowe MO, Petry M, Schuster-Gossler K, Bürger A, Ericson J, Kispert A (Jun 2005). "Tbx20 is essential for cardiac chamber differentiation and repression of Tbx2". Development. 132 (12): 2697–707. doi:10.1242/dev.01854. PMID 15901664.
7. Stennard FA, Costa MW, Lai D, Biben C, Furtado MB, Solloway MJ, McCulley DJ, Leimena C, Preis JI, Dunwoodie SL, Elliott DE, Prall OW, Black BL, Fatkin D, Harvey RP (May 2005). "Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation". Development. 132 (10): 2451–62. doi:10.1242/dev.01799. PMID 15843414.
8. Takeuchi JK, Mileikovskaia M, Koshiba-Takeuchi K, Heidt AB, Mori AD, Arruda EP, Gertsenstein M, Georges R, Davidson L, Mo R, Hui CC, Henkelman RM, Nemer M, Black BL, Nagy A, Bruneau BG (May 2005). "Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development". Development. 132 (10): 2463–74. doi:10.1242/dev.01827. PMID 15843409.
9. Qian L, Mohapatra B, Akasaka T, Liu J, Ocorr K, Towbin JA, Bodmer R (Dec 2008). "Transcription factor neuromancer/TBX20 is required for cardiac function in Drosophila with implications for human heart disease". Proceedings of the National Academy of Sciences of the United States of America. 105 (50): 19833–8. doi:10.1073/pnas.0808705105. PMC 2605007. PMID 19074289.
10. Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML, Butler TL, Hyun C, Guo G, Otway R, Mackay JP, Waddell LB, Cole AD, Hayward C, Keogh A, Macdonald P, Griffiths L, Fatkin D, Sholler GF, Zorn AM, Feneley MP, Winlaw DS, Harvey RP (Aug 2007). "Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy". American Journal of Human Genetics. 81 (2): 280–91. doi:10.1086/519530. PMC 1950799. PMID 17668378.
11. Liu C, Shen A, Li X, Jiao W, Zhang X, Li Z (1 November 2008). "T-box transcription factor TBX20 mutations in Chinese patients with congenital heart disease". European Journal of Medical Genetics. 51 (6): 580–7. doi:10.1016/j.ejmg.2008.09.001. PMID 18834961.
12. Posch MG, Gramlich M, Sunde M, Schmitt KR, Lee SH, Richter S, Kersten A, Perrot A, Panek AN, Al Khatib IH, Nemer G, Mégarbané A, Dietz R, Stiller B, Berger F, Harvey RP, Ozcelik C (Apr 2010). "A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects". Journal of Medical Genetics. 47 (4): 230–5. doi:10.1136/jmg.2009.069997. PMC 2981023. PMID 19762328.
13. Song MR, Shirasaki R, Cai CL, Ruiz EC, Evans SM, Lee SK, Pfaff SL (Dec 2006). "T-Box transcription factor Tbx20 regulates a genetic program for cranial motor neuron cell body migration". Development. 133 (24): 4945–55. doi:10.1242/dev.02694. PMC 5851594. PMID 17119020.
14. Shen T, Aneas I, Sakabe N, Dirschinger RJ, Wang G, Smemo S, Westlund JM, Cheng H, Dalton N, Gu Y, Boogerd CJ, Cai CL, Peterson K, Chen J, Nobrega MA, Evans SM (Dec 2011). "Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function". The Journal of Clinical Investigation. 121 (12): 4640–54. doi:10.1172/JCI59472. PMC 3223071. PMID 22080862.
15. Sakabe NJ, Aneas I, Shen T, Shokri L, Park SY, Bulyk ML, Evans SM, Nobrega MA (May 2012). "Dual transcriptional activator and repressor roles of TBX20 regulate adult cardiac structure and function". Human Molecular Genetics. 21 (10): 2194–204. doi:10.1093/hmg/dds034. PMC 3335310. PMID 22328084.

External links

• Human UniProt entry
• Mouse UniProt entry
• WikiGenes entry