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{{Infobox_gene}}
{{Infobox_gene}}
'''Brachyury''' is a [[protein]] that, in humans, is encoded by the ''TBXT'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: T| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6862| accessdate = }}</ref><ref name="pmid8963900">{{cite journal | vauthors = Edwards YH, Putt W, Lekoape KM, Stott D, Fox M, Hopkinson DA, Sowden J | title = The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27 | journal = Genome Res. | volume = 6 | issue = 3 | pages = 226–33 |date=March 1996 | pmid = 8963900 | doi = 10.1101/gr.6.3.226| url = }}</ref> Brachyury is a [[transcription factor]] within the T-box complex of genes.<ref name="Scholz2002">{{cite journal | vauthors = Scholz CB, Technau U | title = The ancestral role of Brachyury: expression of NemBra1 in the basal cnidarian Nematostella vectensis (Anthozoa) | journal = Dev. Genes Evol. | volume = 212 | issue = 12 | pages = 563–70 |date=January 2003 | pmid = 12536320 | doi = 10.1007/s00427-002-0272-x | url = }}</ref> It has been found in all [[bilateria]]n animals that have been screened, and is also present in the [[cnidaria]].<ref name='Scholz2002'/>
'''Brachyury''' is a [[protein]] that, in humans, is encoded by the ''TBXT'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: T| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6862| access-date = }}</ref><ref name="pmid8963900">{{cite journal | vauthors = Edwards YH, Putt W, Lekoape KM, Stott D, Fox M, Hopkinson DA, Sowden J | title = The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27 | journal = Genome Research | volume = 6 | issue = 3 | pages = 226–33 | date = March 1996 | pmid = 8963900 | doi = 10.1101/gr.6.3.226 }}</ref> Brachyury is a [[transcription factor]] within the T-box complex of genes.<ref name="Scholz2002">{{cite journal | vauthors = Scholz CB, Technau U | title = The ancestral role of Brachyury: expression of NemBra1 in the basal cnidarian Nematostella vectensis (Anthozoa) | journal = Development Genes and Evolution | volume = 212 | issue = 12 | pages = 563–70 | date = January 2003 | pmid = 12536320 | doi = 10.1007/s00427-002-0272-x }}</ref> It has been found in all [[bilateria]]n animals that have been screened, and is also present in the [[cnidaria]].<ref name='Scholz2002'/>


== History ==
== History ==
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In 2018 HGNC updated the human gene name from ''T'' to ''TBXT'', presumably to overcome difficulties associated with searching for a single letter gene symbol. It is assumed that the mouse nomenclature will also be updated in due course.
In 2018 HGNC updated the human gene name from ''T'' to ''TBXT'', presumably to overcome difficulties associated with searching for a single letter gene symbol. It is assumed that the mouse nomenclature will also be updated in due course.


The mouse ''T'' gene was cloned by [[Bernhard Herrmann]] and colleagues<ref name="pmid2154694">{{cite journal | vauthors = Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H | title = Cloning of the T gene required in mesoderm formation in the mouse | journal = Nature | volume = 343 | issue = 6259 | pages = 617–22 |date=February 1990 | pmid = 2154694 | doi = 10.1038/343617a0 | url = | bibcode = 1990Natur.343..617H }}</ref> and proved to encode a 436 amino acid embryonic nuclear [[transcription factor]]. T binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. ''T'' is the founding member of the [[T-box]] family which in mammals currently consists of 18 T-box genes.
The mouse ''T'' gene was cloned by [[Bernhard Herrmann]] and colleagues<ref name="pmid2154694">{{cite journal | vauthors = Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H | title = Cloning of the T gene required in mesoderm formation in the mouse | journal = Nature | volume = 343 | issue = 6259 | pages = 617–22 | date = February 1990 | pmid = 2154694 | doi = 10.1038/343617a0 | bibcode = 1990Natur.343..617H }}</ref> and proved to encode a 436 amino acid embryonic nuclear [[transcription factor]]. T binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. ''T'' is the founding member of the [[T-box]] family which in mammals currently consists of 18 T-box genes.


The crystal structure of the human brachyury protein was solved in 2017 by Opher Gileadi and colleagues at the Structural Genomics Consortium in Oxford.<ref>{{Cite journal|last=Gileadi|first=O.|last2=Bountra|first2=C.|last3=Edwards|first3=A.|last4=Arrowsmith|first4=C. H.|last5=von Delft|first5=F.|last6=Burgess-Brown|first6=N. A.|last7=Shrestha|first7=L.|last8=Krojer|first8=T.|last9=Gavard|first9=A. E.|title=Crystal structure of human Brachyury (T) in complex with DNA|url=https://www.rcsb.org/structure/6F58|journal=To be Published|doi=10.2210/pdb6f58/pdb|year=2017}}</ref>
The crystal structure of the human brachyury protein was solved in 2017 by Opher Gileadi and colleagues at the Structural Genomics Consortium in Oxford.<ref>{{cite journal | vauthors = Gileadi O, Bountra C, Edwards A, Arrowsmith CH, von Delft F, Burgess-Brown NA, Shrestha L, Krojer T, Gavard AE |title=Crystal structure of human Brachyury (T) in complex with DNA|url=https://www.rcsb.org/structure/6F58|journal=To be Published|doi=10.2210/pdb6f58/pdb|year=2017}}</ref>


[[Image:Paul Burridge Brachyury in E7.5.jpg|thumb|right|Brachyury expression in 7.5dpc CD1 mouse embryos]]
[[Image:Paul Burridge Brachyury in E7.5.jpg|thumb|right|Brachyury expression in 7.5dpc CD1 mouse embryos]]


== Role in Development ==
== Role in Development ==
The gene ''brachyury'' appears to have a conserved role in defining the midline of a bilaterian organism,<ref>{{Cite journal| doi = 10.1007/s00427-004-0399-z| pmid = 15034714| year = 2004| last1 = Le Gouar | first1 = M.| last2 = Guillou | first2 = A.| last3 = Vervoort | first3 = M.| title = Expression of a SoxB and a Wnt2/13 gene during the development of the mollusc Patella vulgata.| volume = 214| issue = 5| pages = 250–256| journal = Development Genes and Evolution }}</ref> and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs.<ref name=Lartillot2002>{{cite journal|last1=Lartillot|first1=N|last2=Lespinet|first2=O|last3=Vervoort|first3=M|last4=Adoutte|first4=A|title=Expression pattern of Brachyury in the mollusc Patella vulgata suggests a conserved role in the establishment of the AP axis in Bilateria.|journal=Development|volume=129|issue=6|pages=1411–1421|year=2002|pmid=11880350}}</ref>
The gene ''brachyury'' appears to have a conserved role in defining the midline of a bilaterian organism,<ref>{{cite journal | vauthors = Le Gouar M, Guillou A, Vervoort M | title = Expression of a SoxB and a Wnt2/13 gene during the development of the mollusc Patella vulgata | journal = Development Genes and Evolution | volume = 214 | issue = 5 | pages = 250–6 | date = May 2004 | pmid = 15034714 | doi = 10.1007/s00427-004-0399-z }}</ref> and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs.<ref name=Lartillot2002>{{cite journal | vauthors = Lartillot N, Lespinet O, Vervoort M, Adoutte A | title = Expression pattern of Brachyury in the mollusc Patella vulgata suggests a conserved role in the establishment of the AP axis in Bilateria | journal = Development | volume = 129 | issue = 6 | pages = 1411–21 | date = March 2002 | pmid = 11880350 }}</ref>
Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the [[blastopore]].<ref name='Scholz2002'/> It also defines the mesoderm during gastrulation.<ref>{{Cite journal| doi = 10.1016/S0012-1606(03)00244-6| title = Evolution of Brachyury proteins: identification of a novel regulatory domain conserved within Bilateria| year = 2003| last1 = Marcellini | first1 = S.| journal = Developmental Biology| volume = 260| pages = 352–361| pmid = 12921737| last2 = Technau | first2 = U.| last3 = Smith | first3 = J.|authorlink3=James Cuthbert Smith| last4 = Lemaire | first4 = P.| issue = 2 }}</ref> Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak.<ref>{{Cite journal|title = An ECM substratum allows mouse mesodermal cells isolated from the primitive streak to exhibit motility similar to that inside the embryo and reveals a deficiency in the T/T mutant cells|url = http://dev.biologists.org/content/100/4/587|journal = Development|date = 1987-08-01|issn = 0950-1991|pmid = 3327671|pages = 587–598|volume = 100|issue = 4|first = K.|last = Hashimoto|first2 = H.|last2 = Fujimoto|first3 = N.|last3 = Nakatsuji}}</ref><ref>{{Cite journal|title = Brachyury cooperates with Wnt/β-catenin signalling to elicit primitive-streak-like behaviour in differentiating mouse embryonic stem cells|journal = BMC Biology|date = 2014-08-13|pmc = 4171571|pmid = 25115237|volume = 12|issue = 1|pages = 63|doi = 10.1186/s12915-014-0063-7|first = David A|last = Turner|first2 = Pau|last2 = Rué|first3 = Jonathan P|last3 = Mackenzie|first4 = Eleanor|last4 = Davies|first5 = Alfonso Martinez|last5 = Arias}}</ref>
Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the [[blastopore]].<ref name='Scholz2002'/> It also defines the mesoderm during gastrulation.<ref>{{cite journal | vauthors = Marcellini S, Technau U, Smith JC, Lemaire P | title = Evolution of Brachyury proteins: identification of a novel regulatory domain conserved within Bilateria | journal = Developmental Biology | volume = 260 | issue = 2 | pages = 352–61 | date = August 2003 | pmid = 12921737 | doi = 10.1016/S0012-1606(03)00244-6 | authorlink3 = James Cuthbert Smith }}</ref> Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak.<ref>{{cite journal | vauthors = Hashimoto K, Fujimoto H, Nakatsuji N | title = An ECM substratum allows mouse mesodermal cells isolated from the primitive streak to exhibit motility similar to that inside the embryo and reveals a deficiency in the T/T mutant cells | journal = Development | volume = 100 | issue = 4 | pages = 587–98 | date = August 1987 | pmid = 3327671 | url = http://dev.biologists.org/content/100/4/587 }}</ref><ref>{{cite journal | vauthors = Turner DA, Rué P, Mackenzie JP, Davies E, Martinez Arias A | title = Brachyury cooperates with Wnt/β-catenin signalling to elicit primitive-streak-like behaviour in differentiating mouse embryonic stem cells | journal = BMC Biology | volume = 12 | issue = 1 | pages = 63 | date = August 2014 | pmid = 25115237 | pmc = 4171571 | doi = 10.1186/s12915-014-0063-7 }}</ref>


Transcription of genes required for [[germ layer#Mesoderm|mesoderm]] formation and [[cellular differentiation]].{{Clarify|date=February 2010}}
Transcription of genes required for [[germ layer#Mesoderm|mesoderm]] formation and [[cellular differentiation]].{{Clarify|date=February 2010}}
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=== Cancer ===
=== Cancer ===
Brachyury is implicated in the initiation and/or progression of a number of tumor types including chordoma, [[germ cell tumor]]s, [[hemangioblastoma]], [[Gastrointestinal stromal tumor|GIST]], [[lung cancer]], [[Small-cell carcinoma|small cell carcinoma]] of the lung, [[breast cancer]], [[Colorectal cancer|colon cancer]], [[hepatocellular carcinoma]], [[prostate cancer]], and oral squamous carcinoma.<ref>{{Cite journal|last=Hamilton|first=Duane H.|last2=David|first2=Justin M.|last3=Dominguez|first3=Charli|last4=Palena|first4=Claudia|date=2017|title=Development of cancer vaccines targeting brachyury, a transcription factor associated with tumor EMT|journal=Cells, Tissues, Organs|volume=203|issue=2|pages=128–138|doi=10.1159/000446495|issn=1422-6405|pmc=5381518|pmid=28214895}}</ref>
Brachyury is implicated in the initiation and/or progression of a number of tumor types including chordoma, [[germ cell tumor]]s, [[hemangioblastoma]], [[Gastrointestinal stromal tumor|GIST]], [[lung cancer]], [[Small-cell carcinoma|small cell carcinoma]] of the lung, [[breast cancer]], [[Colorectal cancer|colon cancer]], [[hepatocellular carcinoma]], [[prostate cancer]], and oral squamous carcinoma.<ref>{{cite journal | vauthors = Hamilton DH, David JM, Dominguez C, Palena C | title = Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition | journal = Cells, Tissues, Organs | volume = 203 | issue = 2 | pages = 128–138 | date = 2017 | pmid = 28214895 | pmc = 5381518 | doi = 10.1159/000446495 }}</ref>


Most notably, it has been identified as a definitive diagnostic marker, key driver and therapeutic target for [[chordoma]], a malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. The evidence regarding brachyury's role in chordoma includes:
Most notably, it has been identified as a definitive diagnostic marker, key driver and therapeutic target for [[chordoma]], a malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. The evidence regarding brachyury's role in chordoma includes:


* Brachyury is highly expressed in all chordomas except for the dedifferentiated subtype, which accounts for less than 5% of cases<ref name="Vuj2006">{{cite journal | vauthors = Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM | title = Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas | journal = J. Pathol. | volume = 209 | issue = 2 | pages = 157–65 |date=June 2006 | doi = 10.1002/path.1969 | pmid =16538613 }}</ref>
* Brachyury is highly expressed in all chordomas except for the dedifferentiated subtype, which accounts for less than 5% of cases<ref name="Vuj2006">{{cite journal | vauthors = Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM | title = Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas | journal = The Journal of Pathology | volume = 209 | issue = 2 | pages = 157–65 | date = June 2006 | pmid = 16538613 | doi = 10.1002/path.1969 }}</ref>
* Germ line duplication of the brachyury gene is responsible for familial chordoma.<ref>{{Cite journal|last=Yang|first=Xiaohong R.|last2=Ng|first2=David|last3=Alcorta|first3=David A.|last4=Liebsch|first4=Norbert J.|last5=Sheridan|first5=Eamonn|last6=Li|first6=Sufeng|last7=Goldstein|first7=Alisa M.|last8=Parry|first8=Dilys M.|last9=Kelley|first9=Michael J.|date=November 2009|title=T (brachyury) gene duplication confers major susceptibility to familial chordoma|journal=Nature Genetics|volume=41|issue=11|pages=1176–1178|doi=10.1038/ng.454|issn=1546-1718|pmc=2901855|pmid=19801981}}</ref>
* Germ line duplication of the brachyury gene is responsible for familial chordoma.<ref>{{cite journal | vauthors = Yang XR, Ng D, Alcorta DA, Liebsch NJ, Sheridan E, Li S, Goldstein AM, Parry DM, Kelley MJ | title = T (brachyury) gene duplication confers major susceptibility to familial chordoma | journal = Nature Genetics | volume = 41 | issue = 11 | pages = 1176–8 | date = November 2009 | pmid = 19801981 | pmc = 2901855 | doi = 10.1038/ng.454 }}</ref>
* A germline SNP in brachyury is present in 97% of chordoma patients.<ref>{{Cite journal|last=Pillay|first=Nischalan|last2=Plagnol|first2=Vincent|last3=Tarpey|first3=Patrick S.|last4=Lobo|first4=Samira B.|last5=Presneau|first5=Nadège|last6=Szuhai|first6=Karoly|last7=Halai|first7=Dina|last8=Berisha|first8=Fitim|last9=Cannon|first9=Stephen R.|date=November 2012|title=A common single-nucleotide variant in T is strongly associated with chordoma|journal=Nature Genetics|volume=44|issue=11|pages=1185–1187|doi=10.1038/ng.2419|issn=1546-1718|pmid=23064415}}</ref>
* A germline SNP in brachyury is present in 97% of chordoma patients.<ref>{{cite journal | vauthors = Pillay N, Plagnol V, Tarpey PS, Lobo SB, Presneau N, Szuhai K, Halai D, Berisha F, Cannon SR, Mead S, Kasperaviciute D, Palmen J, Talmud PJ, Kindblom LG, Amary MF, Tirabosco R, Flanagan AM | display-authors = 6 | title = A common single-nucleotide variant in T is strongly associated with chordoma | journal = Nature Genetics | volume = 44 | issue = 11 | pages = 1185–7 | date = November 2012 | pmid = 23064415 | doi = 10.1038/ng.2419 }}</ref>
* Somatic amplifications of brachyury are seen in a subset of sporadic chordomas either by aneuploidy or focal duplication.<ref>{{Cite journal|last=Campbell|first=Peter J.|last2=Flanagan|first2=Adrienne M.|last3=Stratton|first3=Michael R.|last4=Yip|first4=Stephen|last5=Pillay|first5=Nischalan|last6=Tirabosco|first6=Roberto|last7=Amary|first7=M. Fernanda|last8=Phillips|first8=Joanna J.|last9=Sommer|first9=Josh|date=2017-10-12|title=The driver landscape of sporadic chordoma|journal=Nature Communications|volume=8|issue=1|pages=890|doi=10.1038/s41467-017-01026-0|pmid=29026114|pmc=5638846|issn=2041-1723|bibcode=2017NatCo...8..890T}}</ref>
* Somatic amplifications of brachyury are seen in a subset of sporadic chordomas either by aneuploidy or focal duplication.<ref>{{cite journal | vauthors = Tarpey PS, Behjati S, Young MD, Martincorena I, Alexandrov LB, Farndon SJ, Guzzo C, Hardy C, Latimer C, Butler AP, Teague JW, Shlien A, Futreal PA, Shah S, Bashashati A, Jamshidi F, Nielsen TO, Huntsman D, Baumhoer D, Brandner S, Wunder J, Dickson B, Cogswell P, Sommer J, Phillips JJ, Amary MF, Tirabosco R, Pillay N, Yip S, Stratton MR, Flanagan AM, Campbell PJ | display-authors = 6 | title = The driver landscape of sporadic chordoma | journal = Nature Communications | volume = 8 | issue = 1 | pages = 890 | date = October 2017 | pmid = 29026114 | pmc = 5638846 | doi = 10.1038/s41467-017-01026-0 | bibcode = 2017NatCo...8..890T }}</ref>
* Brachyury is the most selectively essential gene in chordoma relative to other cancer types.<ref name="Sharifnia 292–300">{{Cite journal|last=Sharifnia|first=Tanaz|last2=Wawer|first2=Mathias J.|last3=Chen|first3=Ting|last4=Huang|first4=Qing-Yuan|last5=Weir|first5=Barbara A.|last6=Sizemore|first6=Ann|last7=Lawlor|first7=Matthew A.|last8=Goodale|first8=Amy|last9=Cowley|first9=Glenn S.|date=February 2019|title=Small-molecule targeting of brachyury transcription factor addiction in chordoma|journal=Nature Medicine|volume=25|issue=2|pages=292–300|doi=10.1038/s41591-018-0312-3|issn=1546-170X|pmid=30664779}}</ref>
* Brachyury is the most selectively essential gene in chordoma relative to other cancer types.<ref name="Sharifnia 292–300">{{cite journal | vauthors = Sharifnia T, Wawer MJ, Chen T, Huang QY, Weir BA, Sizemore A, Lawlor MA, Goodale A, Cowley GS, Vazquez F, Ott CJ, Francis JM, Sassi S, Cogswell P, Sheppard HE, Zhang T, Gray NS, Clarke PA, Blagg J, Workman P, Sommer J, Hornicek F, Root DE, Hahn WC, Bradner JE, Wong KK, Clemons PA, Lin CY, Kotz JD, Schreiber SL | display-authors = 6 | title = Small-molecule targeting of brachyury transcription factor addiction in chordoma | journal = Nature Medicine | volume = 25 | issue = 2 | pages = 292–300 | date = February 2019 | pmid = 30664779 | doi = 10.1038/s41591-018-0312-3 }}</ref>
* Brachyury is associated with a large [[Super-enhancer|superenhancer]] in chordoma tumors and cell lines, and is the most highly expressed superenhancer-associated transcription factor.<ref name="Sharifnia 292–300"/>
* Brachyury is associated with a large [[Super-enhancer|superenhancer]] in chordoma tumors and cell lines, and is the most highly expressed superenhancer-associated transcription factor.<ref name="Sharifnia 292–300"/>


''Brachyury'' is an important factor in promoting the [[epithelial-mesenchymal transition]] (EMT). Cells that over-express ''brachyury'' have down-regulated expression of the adhesion molecule [[E-cadherin]], which allows them to undergo EMT. This process is at least partially mediated by the transcription factors [[AKT]]<ref name="ReferenceA">Du R, Wu S, Lv H, et al. Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. J Exp Clin Canc Res. 2014;33:105. doi: 10.1186/s13046-014-0105-6.</ref> and Snail.<ref name="ReferenceB">Sun SR, Sun WJ, Xia L, et al. The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression. J Cell Commun Signal. 2014; 12:76. doi:10.1186/s12964-014-0076-4.</ref>
''Brachyury'' is an important factor in promoting the [[epithelial-mesenchymal transition]] (EMT). Cells that over-express ''brachyury'' have down-regulated expression of the adhesion molecule [[E-cadherin]], which allows them to undergo EMT. This process is at least partially mediated by the transcription factors [[AKT]]<ref name="Du_2014">{{cite journal | vauthors = Du R, Wu S, Lv X, Fang H, Wu S, Kang J | title = Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma | journal = Journal of Experimental & Clinical Cancer Research : CR | volume = 33 | issue = | pages = 105 | date = December 2014 | pmid = 25499255 | pmc = 4279691 | doi = 10.1186/s13046-014-0105-6 }}</ref> and Snail.<ref name="Sun_2014">{{cite journal | vauthors = Sun S, Sun W, Xia L, Liu L, Du R, He L, Li R, Wang H, Huang C | title = The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression | journal = Cell Communication and Signaling : CCS | volume = 12 | issue = | pages = 76 | date = November 2014 | pmid = 25433496 | pmc = 4261244 | doi = 10.1186/s12964-014-0076-4 }}</ref>


Overexpression of ''brachyury'' has been linked to [[Hepatocellular carcinoma]] (HCC, also called malignant hepatoma), a common type of liver cancer. While ''brachyury'' is promoting EMT, it can also induce [[metastasis]] of HCC cells. ''Brachyury'' expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future.<ref name="ReferenceA"/>
Overexpression of ''brachyury'' has been linked to [[Hepatocellular carcinoma]] (HCC, also called malignant hepatoma), a common type of liver cancer. While ''brachyury'' is promoting EMT, it can also induce [[metastasis]] of HCC cells. ''Brachyury'' expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future.<ref name="Du_2014"/>


=== Other Diseases ===
=== Other diseases ===
Overexpression of ''brachyury'' may play a part in EMT associated with benign disease such as renal [[fibrosis]].<ref name="ReferenceB" />
Overexpression of ''brachyury'' may play a part in EMT associated with benign disease such as renal [[fibrosis]].<ref name="Sun_2014" />


== Role as a Therapeutic Target ==
== Role as a therapeutic target ==
Because brachyury is expressed in tumors but not in normal adult tissues it has been proposed as a potential drug target with applicability across tumor types. In particular, brachyury-specific peptides are presented on HLA receptors of cells in which it is expressed, representing a tumor specific antigen. Various therapeutic vaccines have been developed which are intended to stimulate an immune response to brachyury expressing cells.<ref>{{Cite journal|last=Hamilton|first=Duane H.|last2=David|first2=Justin M.|last3=Dominguez|first3=Charli|last4=Palena|first4=Claudia|date=2017|title=Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition|journal=Cells, Tissues, Organs|volume=203|issue=2|pages=128–138|doi=10.1159/000446495|issn=1422-6421|pmc=5381518|pmid=28214895}}</ref>
Because brachyury is expressed in tumors but not in normal adult tissues it has been proposed as a potential drug target with applicability across tumor types. In particular, brachyury-specific peptides are presented on HLA receptors of cells in which it is expressed, representing a tumor specific antigen. Various therapeutic vaccines have been developed which are intended to stimulate an immune response to brachyury expressing cells.<ref>{{cite journal | vauthors = Hamilton DH, David JM, Dominguez C, Palena C | title = Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition | journal = Cells, Tissues, Organs | volume = 203 | issue = 2 | pages = 128–138 | date = 2017 | pmid = 28214895 | pmc = 5381518 | doi = 10.1159/000446495 }}</ref>


==See also==
== See also ==
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{{div col|colwidth=30em}}
*[[Homeobox protein NANOG]]
*[[Homeobox protein NANOG]]
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==References==
== References ==
{{reflist}}
{{reflist}}


==Further reading ==
==Further reading ==
{{Refbegin}}
{{Refbegin}}
* {{cite journal | vauthors = Yoshikawa T, Piao Y, Zhong J, Matoba R, Carter MG, Wang Y, Goldberg I, Ko MS | title = High-throughput screen for genes predominantly expressed in the ICM of mouse blastocysts by whole mount in situ hybridization | journal = Gene Expr. Patterns | volume = 6 | issue = 2 | pages = 213–24 |date=January 2006 | pmid = 16325481 | pmc = 1850761 | doi = 10.1016/j.modgep.2005.06.003 | url = }}
* {{cite journal | vauthors = Yoshikawa T, Piao Y, Zhong J, Matoba R, Carter MG, Wang Y, Goldberg I, Ko MS | title = High-throughput screen for genes predominantly expressed in the ICM of mouse blastocysts by whole mount in situ hybridization | journal = Gene Expression Patterns | volume = 6 | issue = 2 | pages = 213–24 | date = January 2006 | pmid = 16325481 | pmc = 1850761 | doi = 10.1016/j.modgep.2005.06.003 }}
* {{cite journal |url=http://deepblue.lib.umich.edu/bitstream/handle/2027.42/42140/335-8-11-799_8n11p799.pdf;jsessionid=6BA755F775C7632A8CF1E67036AF792F?sequence=1 |title=Mutation watch: Mouse brachyury (T), the T-box gene family, and human disease. |author=Meisler |year=1997}}
* {{cite journal |url=http://deepblue.lib.umich.edu/bitstream/handle/2027.42/42140/335-8-11-799_8n11p799.pdf;jsessionid=6BA755F775C7632A8CF1E67036AF792F?sequence=1 |title=Mutation watch: Mouse brachyury (T), the T-box gene family, and human disease. |author=Meisler |year=1997}}
{{Refend}}
{{Refend}}


== External links ==
== External links ==
*[https://www.proteinatlas.org/ENSG00000164458-T/cell Protein Atlas entry for Brachyury]
* [https://www.proteinatlas.org/ENSG00000164458-T/cell Protein Atlas entry for Brachyury]
*[http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=markerDetail&key=13727 Mouse Genome Informatics entry for Brachyury]
* [http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=markerDetail&key=13727 Mouse Genome Informatics entry for Brachyury]
* [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR002070 European Bioinformatics Institute InterPro entry for Brachyury]
* [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR002070 European Bioinformatics Institute InterPro entry for Brachyury]
* [http://www.ihop-net.org/UniPub/iHOP/gs/124990.html Information Hyperlinked Over Proteins entry for Brachyury]
* [http://www.ihop-net.org/UniPub/iHOP/gs/124990.html Information Hyperlinked Over Proteins entry for Brachyury]

Revision as of 04:05, 24 April 2019

TBXT
Identifiers
AliasesTBXT, T, brachyury homolog (mouse), SAVA, TFT, T brachyury transcription factor, T-box transcription factor T, T
External IDsOMIM: 601397 MGI: 98472 HomoloGene: 2393 GeneCards: TBXT
Orthologs
SpeciesHumanMouse
Entrez

6862

20997

Ensembl

ENSG00000164458

ENSMUSG00000062327

UniProt

O15178

P20293

RefSeq (mRNA)

NM_001270484
NM_003181
NM_001366285
NM_001366286

NM_009309

RefSeq (protein)

NP_001257413
NP_003172
NP_001353214
NP_001353215

NP_033335

Location (UCSC)Chr 6: 166.16 – 166.17 MbChr 17: 8.65 – 8.66 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Brachyury is a protein that, in humans, is encoded by the TBXT gene.[5][6] Brachyury is a transcription factor within the T-box complex of genes.[7] It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.[7]

History

The brachyury mutation was first described in mice by Nadezhda Alexandrovna Dobrovolskaya-Zavadskaya in 1927 as a mutation that affected tail length and sacral vertebrae in heterozygous animals. In homozygous animals the brachyury mutation is lethal at around embryonic day 10 due to defects in mesoderm formation, notochord differentiation and the absence of structures posterior to the forelimb bud (Dobrovolskaïa-Zavadskaïa, 1927). The name brachyury comes from the Greek brakhus meaning short and oura meaning tail.

In 2018 HGNC updated the human gene name from T to TBXT, presumably to overcome difficulties associated with searching for a single letter gene symbol. It is assumed that the mouse nomenclature will also be updated in due course.

The mouse T gene was cloned by Bernhard Herrmann and colleagues[8] and proved to encode a 436 amino acid embryonic nuclear transcription factor. T binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. T is the founding member of the T-box family which in mammals currently consists of 18 T-box genes.

The crystal structure of the human brachyury protein was solved in 2017 by Opher Gileadi and colleagues at the Structural Genomics Consortium in Oxford.[9]

Brachyury expression in 7.5dpc CD1 mouse embryos

Role in Development

The gene brachyury appears to have a conserved role in defining the midline of a bilaterian organism,[10] and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs.[11] Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore.[7] It also defines the mesoderm during gastrulation.[12] Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak.[13][14]

Transcription of genes required for mesoderm formation and cellular differentiation.[clarification needed]

Brachyury has also been shown to help establish the cervical vertebral blueprint during fetal development. The number of cervical vertebrae is highly conserved among all mammals; however a spontaneous vertebral and spinal dysplasia (VSD) mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven.[15]

Expression

In mice T is expressed in the inner cell mass of the blastocyst stage embryo (but not in the majority of mouse embryonic stem cells) followed by the primitive streak (see image). In later development expression is localised to the node and notochord.

In Xenopus laevis Xbra (the Xenopus T homologue, also recently renamed t) is expressed in the mesodermal marginal zone of the pre-gastrula embryo followed by localisation to the blastopore and notochord at the mid-gastrula stage.

Orthologs

The Danio rerio ortholog is known as ntl (no tail)

Role in Disease

Cancer

Brachyury is implicated in the initiation and/or progression of a number of tumor types including chordoma, germ cell tumors, hemangioblastoma, GIST, lung cancer, small cell carcinoma of the lung, breast cancer, colon cancer, hepatocellular carcinoma, prostate cancer, and oral squamous carcinoma.[16]

Most notably, it has been identified as a definitive diagnostic marker, key driver and therapeutic target for chordoma, a malignant tumor that arises from remnant notochordal cells lodged in the vertebrae. The evidence regarding brachyury's role in chordoma includes:

  • Brachyury is highly expressed in all chordomas except for the dedifferentiated subtype, which accounts for less than 5% of cases[17]
  • Germ line duplication of the brachyury gene is responsible for familial chordoma.[18]
  • A germline SNP in brachyury is present in 97% of chordoma patients.[19]
  • Somatic amplifications of brachyury are seen in a subset of sporadic chordomas either by aneuploidy or focal duplication.[20]
  • Brachyury is the most selectively essential gene in chordoma relative to other cancer types.[21]
  • Brachyury is associated with a large superenhancer in chordoma tumors and cell lines, and is the most highly expressed superenhancer-associated transcription factor.[21]

Brachyury is an important factor in promoting the epithelial-mesenchymal transition (EMT). Cells that over-express brachyury have down-regulated expression of the adhesion molecule E-cadherin, which allows them to undergo EMT. This process is at least partially mediated by the transcription factors AKT[22] and Snail.[23]

Overexpression of brachyury has been linked to Hepatocellular carcinoma (HCC, also called malignant hepatoma), a common type of liver cancer. While brachyury is promoting EMT, it can also induce metastasis of HCC cells. Brachyury expression is a prognostic biomarker for HCC, and the gene may be a target for cancer treatments in the future.[22]

Other diseases

Overexpression of brachyury may play a part in EMT associated with benign disease such as renal fibrosis.[23]

Role as a therapeutic target

Because brachyury is expressed in tumors but not in normal adult tissues it has been proposed as a potential drug target with applicability across tumor types. In particular, brachyury-specific peptides are presented on HLA receptors of cells in which it is expressed, representing a tumor specific antigen. Various therapeutic vaccines have been developed which are intended to stimulate an immune response to brachyury expressing cells.[24]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000164458 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062327 – 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. ^ "Entrez Gene: T".
  6. ^ Edwards YH, Putt W, Lekoape KM, Stott D, Fox M, Hopkinson DA, Sowden J (March 1996). "The human homolog T of the mouse T(Brachyury) gene; gene structure, cDNA sequence, and assignment to chromosome 6q27". Genome Research. 6 (3): 226–33. doi:10.1101/gr.6.3.226. PMID 8963900.
  7. ^ a b c Scholz CB, Technau U (January 2003). "The ancestral role of Brachyury: expression of NemBra1 in the basal cnidarian Nematostella vectensis (Anthozoa)". Development Genes and Evolution. 212 (12): 563–70. doi:10.1007/s00427-002-0272-x. PMID 12536320.
  8. ^ Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H (February 1990). "Cloning of the T gene required in mesoderm formation in the mouse". Nature. 343 (6259): 617–22. Bibcode:1990Natur.343..617H. doi:10.1038/343617a0. PMID 2154694.
  9. ^ Gileadi O, Bountra C, Edwards A, Arrowsmith CH, von Delft F, Burgess-Brown NA, Shrestha L, Krojer T, Gavard AE (2017). "Crystal structure of human Brachyury (T) in complex with DNA". To be Published. doi:10.2210/pdb6f58/pdb.
  10. ^ Le Gouar M, Guillou A, Vervoort M (May 2004). "Expression of a SoxB and a Wnt2/13 gene during the development of the mollusc Patella vulgata". Development Genes and Evolution. 214 (5): 250–6. doi:10.1007/s00427-004-0399-z. PMID 15034714.
  11. ^ Lartillot N, Lespinet O, Vervoort M, Adoutte A (March 2002). "Expression pattern of Brachyury in the mollusc Patella vulgata suggests a conserved role in the establishment of the AP axis in Bilateria". Development. 129 (6): 1411–21. PMID 11880350.
  12. ^ Marcellini S, Technau U, Smith JC, Lemaire P (August 2003). "Evolution of Brachyury proteins: identification of a novel regulatory domain conserved within Bilateria". Developmental Biology. 260 (2): 352–61. doi:10.1016/S0012-1606(03)00244-6. PMID 12921737.
  13. ^ Hashimoto K, Fujimoto H, Nakatsuji N (August 1987). "An ECM substratum allows mouse mesodermal cells isolated from the primitive streak to exhibit motility similar to that inside the embryo and reveals a deficiency in the T/T mutant cells". Development. 100 (4): 587–98. PMID 3327671.
  14. ^ Turner DA, Rué P, Mackenzie JP, Davies E, Martinez Arias A (August 2014). "Brachyury cooperates with Wnt/β-catenin signalling to elicit primitive-streak-like behaviour in differentiating mouse embryonic stem cells". BMC Biology. 12 (1): 63. doi:10.1186/s12915-014-0063-7. PMC 4171571. PMID 25115237.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Kromik A, Ulrich R, Kusenda M, et al. The mammalian cervical vertebrae blueprint depends on the T (brachyury) Gene. Genetics. 2015;199(3):183+. doi:10.1534/genetics.114.169680.
  16. ^ Hamilton DH, David JM, Dominguez C, Palena C (2017). "Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition". Cells, Tissues, Organs. 203 (2): 128–138. doi:10.1159/000446495. PMC 5381518. PMID 28214895.
  17. ^ Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM (June 2006). "Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas". The Journal of Pathology. 209 (2): 157–65. doi:10.1002/path.1969. PMID 16538613.
  18. ^ Yang XR, Ng D, Alcorta DA, Liebsch NJ, Sheridan E, Li S, Goldstein AM, Parry DM, Kelley MJ (November 2009). "T (brachyury) gene duplication confers major susceptibility to familial chordoma". Nature Genetics. 41 (11): 1176–8. doi:10.1038/ng.454. PMC 2901855. PMID 19801981.
  19. ^ Pillay N, Plagnol V, Tarpey PS, Lobo SB, Presneau N, Szuhai K, et al. (November 2012). "A common single-nucleotide variant in T is strongly associated with chordoma". Nature Genetics. 44 (11): 1185–7. doi:10.1038/ng.2419. PMID 23064415.
  20. ^ Tarpey PS, Behjati S, Young MD, Martincorena I, Alexandrov LB, Farndon SJ, et al. (October 2017). "The driver landscape of sporadic chordoma". Nature Communications. 8 (1): 890. Bibcode:2017NatCo...8..890T. doi:10.1038/s41467-017-01026-0. PMC 5638846. PMID 29026114.
  21. ^ a b Sharifnia T, Wawer MJ, Chen T, Huang QY, Weir BA, Sizemore A, et al. (February 2019). "Small-molecule targeting of brachyury transcription factor addiction in chordoma". Nature Medicine. 25 (2): 292–300. doi:10.1038/s41591-018-0312-3. PMID 30664779.
  22. ^ a b Du R, Wu S, Lv X, Fang H, Wu S, Kang J (December 2014). "Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma". Journal of Experimental & Clinical Cancer Research : CR. 33: 105. doi:10.1186/s13046-014-0105-6. PMC 4279691. PMID 25499255.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ a b Sun S, Sun W, Xia L, Liu L, Du R, He L, Li R, Wang H, Huang C (November 2014). "The T-box transcription factor Brachyury promotes renal interstitial fibrosis by repressing E-cadherin expression". Cell Communication and Signaling : CCS. 12: 76. doi:10.1186/s12964-014-0076-4. PMC 4261244. PMID 25433496.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  24. ^ Hamilton DH, David JM, Dominguez C, Palena C (2017). "Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition". Cells, Tissues, Organs. 203 (2): 128–138. doi:10.1159/000446495. PMC 5381518. PMID 28214895.

Further reading

External links

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