T-box transcription factor T
T-box transcription factor T, also known as Brachyury protein, is encoded for in humans and other apes by the TBXT gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian animals that have been screened, as well as the freshwater cnidarian Hydra.
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. 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.
Tbxt was cloned by Bernhard Herrmann and colleagues and proved to encode a 436 amino acid embryonic nuclear transcription factor. Tbxt binds to a specific DNA element, a near palindromic sequence TCACACCT through a region in its N-terminus, called the T-box. Tbxt 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.
Image:Paul Burridge Brachyury in E7.5.jpg|thumb|right|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, and thus the establishment of the anterior-posterior axis; this function is apparent in chordates and molluscs.Its ancestral role, or at least the role it plays in the Cnidaria, appears to be in defining the blastopore. It also defines the mesoderm during gastrulation. Tissue-culture based techniques have demonstrated one of its roles may be in controlling the velocity of cells as they leave the primitive streak. It effects transcription of genes required for mesoderm formation and cellular differentiation.
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 mutation in this gene has been associated with the development of six or fewer cervical vertebrae instead of the usual seven.
Expression
In mice, T is expressed in the inner cell mass of the blastocyst stage embryo followed by the primitive streak. In later development, expression is localised to the node and notochord.In Xenopus laevis, Xbra 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.Role in hominid evolution
Tail development
TBXT is a transcription factor observed in vertebrate organisms. As such, it is primarily responsible for the genotype that codes for tail formation due to its observed role in axial development and the construction of posterior mesoderm within the lumbar and sacral regions. TBXT transcribes genes that form notochord cells, which are responsible for the flexibility, length, and balance of the spine, including tail vertebrae. Because of the role that the transcription factor plays in spinal development, it is cited as being the protein that is primarily responsible for tail development in mammals. However, due to being a genetically-induced phenotype, it is possible for tail-encoding material to be effectively silenced by mutation. This is the mechanism by which the ntl ortholog developed in the hominidae taxa.Alu elements
In particular, an Alu element in TBXT is responsible for the taillessness ortholog. An Alu element is evolved, mobile RNA that is exclusively in primates. These elements are capable of mobilizing around a genome, making Alu elements transposons. The Alu element that is observed to catalyze taillessness in TBXT is AluY. While normally Alu elements are not individually impactful, the presence of another Alu element active in TBXT, AluSx1, is coded such that its nucleotides are the inverse of AluYAs a result of the effect on TBXT's tail-encoding material that AluY has alongside AluSx1, isoform TBXT-Δexon6 is created. Isoforms are often a result of mutation, polymorphism, and recombination, and happen to share often highly similar functions to the proteins they derive from. However often they can have some key differences due to either containing added instructions or missing instructions the original protein is known to possess. TBXT-Δexon6 falls into this category, as it is an isoform that lacks the ability to process the code that enables proper tail formation in TBXT-containing organisms. This is because exon 6's material that helps encode for tail formation is excised from the contents of the transcribed RNA. As a result, it is effectively missing in the isoform, and is thus the key factor in determining the isoform's name. Other common examples of influential isoforms include those involved in AMP-induced protein kinase that insert phosphate groups into specific sites of the cell depending on the subunit.
Speciation
The first insertion of the AluY element occurred approximately 20-25 million years ago, with the earliest hominid ancestor known to exhibit this mutation being the Hominoidea family of apes. Taillessness has become an overwhelmingly dominant phenotype, such that it contributes to speciation. Over time, the mutation occurred more regularly due to the influence of natural selection and fixation to stabilize and expand its presence in the ape gene pool prior to the eventual speciation of homo sapiens. There are several potential reasons for why taillessness has become the standard phenotype in the Hominidae taxa that offset the genetically disadvantageous aspects of tail mitigation, but little is known with certainty. Some experts hypothesize that taillessness contributes to a stronger, more upright stance. The stance observed by primates with a smaller lumbar is seen to be effective. Grounded mobility and maintaining balance in climbing are more feasible given the evenly distributed body weight observed in hominids. The presence of an additional appendage can also mean another appendage for predators to grab, and one that also consumes energy to move and takes up more space.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. It is among the genes most differentially expressed in cancer compared to normal tissues.In breast cancer, brachyury expression is associated with recurrence, metastasis and reduced survival. It is also associated with resistance to tamoxifen and to cytotoxic chemotherapy.
In lung cancer, brachyury expression is associated with recurrence and decreased survival. It is also associated with resistance to cytotoxic chemotherapy, radiation, and EGFR kinase inhibitors.
In prostate cancer, brachyury expression is associated with Gleason score, perineural, invasion and capsular invasion.
In addition to its role in common cancers, brachyury has been identified as a definitive diagnostic marker, key driver and therapeutic target for chordoma, a rare 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.
- Germ line duplication of the brachyury gene is responsible for familial chordoma.
- A germline SNP in brachyury is present in 97% of chordoma patients.
- Somatic amplifications of brachyury are seen in a subset of sporadic chordomas either by aneuploidy or focal duplication.
- Brachyury is the most selectively essential gene in chordoma relative to other cancer types.
- Brachyury is associated with a large superenhancer in chordoma tumors and cell lines, and is the most highly expressed superenhancer-associated transcription factor.
Overexpression of brachyury has been linked to hepatocellular carcinoma, 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.