Affinage

TBX15

T-box transcription factor TBX15 · UniProt Q96SF7

Length
602 aa
Mass
65.8 kDa
Annotated
2026-06-10
34 papers in source corpus 19 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBX15 is a T-box transcription factor that patterns mesenchymal progenitor populations during skeletal and dermal development and later governs metabolic identity in adipose tissue and muscle (PMID:14737183, PMID:15652702, PMID:31352005). It homo- and heterodimerizes with TBX18, binds combinations of T half-sites, and represses transcription through Groucho corepressors, with separable domains for nuclear localization, DNA binding, and transcriptional modulation (PMID:17584735). In development, TBX15 expression in dorsolateral mesenchyme sets dorsoventral positional identity of the dermis by constraining Agouti expression, drives proliferation of skeletal progenitors and prehypertrophic chondrocytes to control bone size and shape, and acts within genetic networks shaping the shoulder girdle (PMID:14737183, PMID:15652702, PMID:15728667). It functions in part by occupying T-box sites that are subject to competition with other T-box proteins such as TBX6 (PMID:20832395). Beyond repression, TBX15 directly activates target promoters confirmed by ChIP, including PRDM16 to drive the brown/brite adipocyte thermogenic program, ADAMTS2 in palatal mesenchyme, and TXNDC5 in glioma (PMID:31352005, PMID:36124393, PMID:38327797). In metabolism, TBX15 marks and promotes a glycolytic state—specifying glycolytic myofibers via AMPK/IGF2 signaling and shifting adipocyte metabolism toward glycolysis—while regulating an adipose gene network including PPARG and KLF15 (PMID:26299309, PMID:28847884, PMID:34340684). TBX15 transcription is itself controlled, being activated by NF-κBp65 in response to TNF-α and repressed by PDX1 in a promoter-methylation-dependent manner (PMID:27327083, PMID:20962579). Human loss-of-function mutations cause Cousin syndrome through protein destabilization or cytoplasmic mislocalization that depletes functional TBX15 (PMID:19068278, PMID:41904889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2004 High

    Established that TBX15 provides an early positional cue, answering how dorsoventral dermal and pigmentation boundaries are set in the embryo.

    Evidence Targeted knockout, transplantation, and fate-mapping in mouse embryos showing dorsal displacement of Agouti expression

    PMID:14737183

    Open questions at the time
    • Direct transcriptional targets mediating dermal patterning not identified
    • Whether Agouti regulation is direct or indirect unresolved
  2. 2005 High

    Defined TBX15 as a controller of progenitor cell number, showing its developmental role operates through proliferation rather than fate alone.

    Evidence Tbx15-null mouse histology and proliferation assays across skeletal compartments

    PMID:15652702

    Open questions at the time
    • Downstream cell-cycle targets not identified
    • Mechanism linking TBX15 to proliferation unknown
  3. 2005 Medium

    Placed TBX15 within a genetic patterning network for the shoulder girdle, defining epistatic partners.

    Evidence Compound mutant genetic epistasis with Gli3, Alx4, and Cart1 in mice

    PMID:15728667

    Open questions at the time
    • Genetic interactions do not establish direct molecular relationships
    • No shared target genes defined
  4. 2007 High

    Resolved the biochemical mode of action: how TBX15 binds DNA and represses transcription.

    Evidence In vitro DNA binding, luciferase reporters, co-IP, and domain mutagenesis showing homo/heterodimerization with TBX18 and Groucho-dependent repression

    PMID:17584735

    Open questions at the time
    • Endogenous genomic binding sites not mapped
    • Repression versus activation context not reconciled
  5. 2008 High

    Linked TBX15 to human disease and clarified the loss-of-function mechanism at the protein level.

    Evidence Human genetic analysis of Cousin syndrome plus in vitro DNA binding and protein degradation assays

    PMID:19068278

    Open questions at the time
    • Tissue-specific consequences of protein loss not detailed
    • Target genes deregulated in patients unknown
  6. 2010 Medium

    Showed TBX15 competes with other T-box factors at shared sites, explaining how mesoderm positional information is encoded.

    Evidence Tbx6 misexpression transgenic mice and in vitro luciferase competition assays

    PMID:20832395

    Open questions at the time
    • Competition shown in vitro; endogenous co-occupancy not demonstrated
    • Specific target promoters limited
  7. 2011 High

    Opened the metabolic dimension of TBX15, showing it suppresses adipocyte differentiation and mitochondrial function.

    Evidence Stable overexpression in 3T3-L1 cells with respirometry, lipogenesis/lipolysis, and triglyceride assays

    PMID:21282637

    Open questions at the time
    • Overexpression model; physiological relevance addressed later
    • Direct transcriptional targets not defined here
  8. 2011 Medium

    Identified an upstream epigenetic repressor of TBX15, connecting its promoter methylation to PDX1.

    Evidence Bisulfite/pyrosequencing methylation analysis and PDX1 luciferase reporter assays

    PMID:20962579

    Open questions at the time
    • Single method for mechanism
    • Physiological context of PDX1 repression not established
  9. 2012 Medium

    Refined TBX15's adipose role by showing it is required for the brown/brite adipogenic program in a cell-type-specific manner.

    Evidence siRNA knockdown in primary brown, inguinal, and epididymal adipocyte precursors with qPCR

    PMID:22912368

    Open questions at the time
    • Direct versus indirect regulation of brown markers unresolved at this stage
    • Knockdown only
  10. 2015 High

    Established TBX15 as a determinant of glycolytic myofiber identity and whole-body energetics via AMPK/IGF2.

    Evidence Conditional knockout mice with fiber-type immunostaining, contractility, metabolic phenotyping, AMPK Western blot, and Igf2 qPCR

    PMID:26299309

    Open questions at the time
    • Whether Igf2 is a direct TBX15 target not shown
    • Mechanism of AMPK activation not defined
  11. 2015 Medium

    Extended TBX15 to cancer cell survival, defining an anti-apoptotic function.

    Evidence Overexpression and siRNA knockdown in thyroid cancer cells with Bax/Bcl2/Bcl-XL Western blot and apoptosis assays

    PMID:26216026

    Open questions at the time
    • Direct transcriptional targets of apoptosis regulation not identified
    • Single lab, single cancer type
  12. 2016 Medium

    Identified a direct inflammatory upstream input, showing NF-κB activates TBX15 transcription.

    Evidence ChIP and luciferase reporter assays with TNF-α stimulation defining two functional NF-κB sites

    PMID:27327083

    Open questions at the time
    • Physiological significance of TNF-α-driven TBX15 induction unclear
    • Downstream consequences not traced
  13. 2017 Medium

    Showed TBX15 is sufficient to impose glycolytic metabolism in adipocytes, linking its expression domain to metabolic phenotype.

    Evidence Subpopulation isolation, ECAR/OCR metabolic profiling, and overexpression in cultured adipocytes

    PMID:28847884

    Open questions at the time
    • Direct metabolic gene targets not defined
    • Overexpression-based sufficiency
  14. 2019 High

    Provided the direct molecular link from TBX15 to thermogenesis by identifying PRDM16 as a directly bound, regulated target.

    Evidence Adipose-specific conditional knockout with ChIP on the Prdm16 promoter and cold/β3-agonist challenge

    PMID:31352005

    Open questions at the time
    • Reconciliation of activation (PRDM16) with prior Groucho-dependent repression not addressed
    • Cofactors at PRDM16 promoter unknown
  15. 2021 Medium

    Defined a TBX15-driven regulatory cascade controlling autophagy, glycolysis, and chemoresistance in breast cancer.

    Evidence Luciferase reporter, KIF2C-PKM2 co-IP, ubiquitination, and ECAR/OCR assays placing TBX15 upstream of miR-152/KIF2C/PKM2

    PMID:34663310

    Open questions at the time
    • Multi-step pathway from a single lab
    • Direct binding of TBX15 to miR-152 locus not confirmed by ChIP
  16. 2021 Medium

    Positioned TBX15 as a trans-regulator of a human adipose gene network relevant to body-fat distribution.

    Evidence siRNA knockdown in human primary preadipocytes with RNA-seq identifying 130 network genes including PPARG and KLF15

    PMID:34340684

    Open questions at the time
    • Direct versus indirect targets within the network not distinguished
    • No ChIP in human cells
  17. 2022 Medium

    Identified ADAMTS2 as a direct TBX15 target in palatal mesenchyme, extending its developmental gene regulation.

    Evidence ChIP, co-transfection reporter, and immunofluorescence co-localization at E13.5

    PMID:36124393

    Open questions at the time
    • Functional consequence of ADAMTS2 activation in palatogenesis not tested
    • Single lab
  18. 2024 Medium

    Established a TBX15→TXNDC5 axis driving glioma malignancy and tumor immune microenvironment remodeling.

    Evidence shRNA silencing with TXNDC5 rescue, in vitro invasion/migration assays, and in vivo tumor model

    PMID:38327797

    Open questions at the time
    • Direct binding of TBX15 to TXNDC5 promoter via ChIP not shown
    • Mechanism of macrophage M2 polarization control indirect
  19. 2024 Medium

    Genome-wide mapping of TBX15 binding sites in preadipocytes, defining a direct target set with unexpected immune-pathway enrichment.

    Evidence ChIP-sequencing in TBX15-overexpressing 3T3-L1 cells integrated with knockout adipose RNA-seq (preprint)

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Overexpression context may bias binding
    • Functional validation of immune-pathway targets pending
  20. 2026 Medium

    Linked a new truncating TBX15 variant to palatal bone formation defects through protein mislocalization, extending the loss-of-function spectrum.

    Evidence Localization and transcriptional activity assays of p.Gln411Ter variant with snRNA-seq and immunofluorescence

    PMID:41904889

    Open questions at the time
    • Direct osteogenic targets in palate not identified
    • Single variant, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TBX15 switches between Groucho-dependent repression and direct promoter activation, and which cofactors dictate target choice across developmental versus metabolic contexts, remains unresolved.
  • No structural model of context-dependent cofactor recruitment
  • Genome-wide direct targets in vivo not consolidated across tissues
  • Mechanistic basis for activation versus repression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
TBX18TLE

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Tbx15 loss of function in dorsal mesenchyme leads to dorsal displacement of Agouti expression, establishing that early embryonic Tbx15 expression in dorsolateral mesenchyme provides an instructional cue that sets the future positional identity of dorsal dermis and controls the dorsoventral pigmentation boundary. Targeted knockout allele, transplantation experiments, fate-mapping studies, embryonic expression analysis PLoS biology High 14737183
2005 Tbx15 null mice display reduced proliferation of prehypertrophic chondrocytes and mesenchymal precursor cells, resulting in reduced bone size and altered bone shape, indicating Tbx15 controls cell number in skeletal progenitor populations during endochondral and intramembranous ossification. Tbx15 null mutant mouse analysis, histology, proliferation assays Mechanisms of development High 15652702
2005 Tbx15 and Gli3 exhibit synergistic genetic interactions in scapular blade formation, and Tbx15 combined with Alx4 and Cart1 mutations indicates epistatic relationships in patterning the shoulder girdle progenitor cells. Double and triple mutant mouse genetic epistasis analysis, marker gene expression Development (Cambridge, England) Medium 15728667
2007 TBX15 and TBX18 proteins homo- and heterodimerize, bind to various combinations of T half-sites, and repress transcription in a Groucho corepressor-dependent manner; functional domains for nuclear localization, DNA binding, and transcriptional modulation were characterized. In vitro DNA binding assays, transcriptional reporter (luciferase) assays, co-immunoprecipitation, domain mutagenesis The Journal of biological chemistry High 17584735
2008 Human TBX15 loss-of-function mutations cause Cousin syndrome; mutant proteins with intact T-box could bind target DNA in vitro but contained a missense stretch directing them to early degradation, markedly reducing cellular protein levels. Human genetic analysis, in vitro DNA binding assay, protein stability/degradation assays American journal of human genetics High 19068278
2010 Ectopic Tbx6 expression in segmented paraxial mesoderm produces Tbx15 null-like phenotypes; in vitro luciferase assays support competition between Tbx6 and endogenous Tbx15 at shared T-box binding sites on target gene promoters. Transgenic misexpression mouse model, in vitro luciferase transcriptional assay Developmental biology Medium 20832395
2011 Overexpression of Tbx15 in 3T3-L1 preadipocytes impairs adipocyte differentiation, reduces triglyceride content, decreases basal lipogenic rate, increases lipolytic rate, reduces mitochondrial mass by 15%, reduces basal mitochondrial respiration by 28%, and reduces maximal respiratory capacity by 45%. Stable overexpression in 3T3-L1 cells, triglyceride assay, respirometry (mitochondrial function assays), lipogenesis/lipolysis assays Proceedings of the National Academy of Sciences of the United States of America High 21282637
2011 PDX1 represses the TBX15 promoter in a methylation-dependent manner, establishing PDX1 as a transcriptional repressor of TBX15 acting through the differentially methylated distal promoter region. Promoter methylation analysis (pyrosequencing, bisulfite), luciferase reporter assay with PDX1 Epigenetics Medium 20962579
2012 siRNA knockdown of Tbx15 in primary brown and inguinal (brite-competent) adipocyte precursors reduces expression of adipogenesis markers (PPARγ, aP2) and brown phenotypic markers (PRDM16, PGC-1α, UCP1), while having no effect on epididymal (non-brite-competent) white adipocytes, establishing Tbx15 as required for the brown/brite adipogenic program. siRNA knockdown in primary mouse adipocyte cultures, qPCR gene expression analysis American journal of physiology. Endocrinology and metabolism Medium 22912368
2015 Ablation of Tbx15 in vivo decreases the number of glycolytic myofibers with a corresponding increase in oxidative fibers, slows myofiber contraction/relaxation, and reduces whole-body oxygen consumption; mechanistically, Tbx15 ablation activates AMPK signaling and decreases Igf2 expression. Conditional knockout mice, fiber-type immunostaining, metabolic phenotyping, contractility assays, Western blot (AMPK), qPCR (Igf2) Nature communications High 26299309
2015 TBX15 overexpression in thyroid cancer cells reduces apoptosis, decreases pro-apoptotic Bax, and increases anti-apoptotic Bcl2 and Bcl-XL; siRNA knockdown increases apoptosis, establishing an anti-apoptotic function for TBX15. Transfection/overexpression, siRNA knockdown, Western blot (Bax, Bcl2, Bcl-XL), apoptosis assay Apoptosis : an international journal on programmed cell death Medium 26216026
2016 NF-κBp65 directly binds to two functional NF-κB binding sites at positions -3302 and -3059 of the TBX15 gene, activating TBX15 expression in response to TNF-α; luciferase reporter assays and ChIP confirm direct NF-κB-mediated transcriptional regulation of TBX15. Luciferase reporter assay, ChIP assay, TNF-α/PMA-ionomycin stimulation, bisulfite sequencing PloS one Medium 27327083
2017 Tbx15 expression is restricted to a glycolytic subpopulation within white adipose tissue, and overexpression of Tbx15 is sufficient to shift adipocyte metabolism toward glycolysis and away from oxidative metabolism in cultured adipocytes. Single-depot subpopulation isolation, metabolic profiling (ECAR/OCR), Tbx15 overexpression in cultured adipocytes Diabetes Medium 28847884
2019 TBX15 directly binds to a key region in the Prdm16 promoter (identified by ChIP), transcriptionally regulating Prdm16, the master gene for adipocyte thermogenesis; adipose-specific Tbx15 knockout impairs adipocyte browning in inguinal fat upon cold exposure and β3-adrenergic stimulation. Adipose-specific conditional knockout (adiponectin-Cre), ChIP assay on Prdm16 promoter, cold-exposure and β3-agonist challenge, metabolic phenotyping Molecular metabolism High 31352005
2021 TBX15 transcriptionally activates miR-152 expression, which in turn targets KIF2C; TBX15/miR-152 overexpression suppresses autophagy and glycolysis in breast cancer cells; KIF2C directly binds PKM2 and prevents PKM2 ubiquitination, stabilizing it and promoting doxorubicin resistance. Luciferase reporter assay, co-immunoprecipitation (KIF2C-PKM2), ECAR/OCR assays, ubiquitination assay, Western blot Cancer cell international Medium 34663310
2021 TBX15 knockdown in human primary preadipocytes changes expression of 130 co-expression network genes including key adipose transcription factors PPARG and KLF15, establishing TBX15 as a trans-regulator of an abdominal obesity-associated adipose gene network. siRNA knockdown in human primary preadipocytes, RNA-seq gene expression profiling Genome medicine Medium 34340684
2022 TBX15 binds to the promoter region of ADAMTS2 and activates its promoter activity, as demonstrated by cellular co-transfection and ChIP assays; TBX15 and ADAMTS2 co-localize in posterior palatal mesenchymal cells at E13.5. ChIP assay, co-transfection reporter assay, immunofluorescence co-localization Human mutation Medium 36124393
2024 TBX15 silencing in glioma cells inhibits proliferation, migration, and invasion, and reduces macrophage recruitment and M2 polarization; TBX15 transcriptionally activates TXNDC5, and rescue assays confirm that TBX15's effects in glioma depend on TXNDC5. shRNA silencing, rescue assay with TXNDC5 overexpression, in vitro migration/invasion/proliferation assays, in vivo tumor model iScience Medium 38327797
2024 TBX15 ChIP-sequencing in mouse 3T3-L1 preadipocytes overexpressing TBX15 identified a set of 52 directly bound target genes enriched for B- and T-cell receptor signalling, JAK-STAT signalling, and haematopoietic cell lineage pathways in adipose tissue. ChIP-sequencing in 3T3-L1 preadipocytes, RNA-seq in knockout adipose tissue, integration of datasets bioRxivpreprint Medium
2026 A truncating TBX15 variant (p.Gln411Ter) causes aberrant cytoplasmic mis-localization of the mutant TBX15 protein and significantly reduced transcriptional activity; TBX15 is expressed in a specific mesenchymal cell population during palatogenesis and co-localizes with osteogenic markers, implicating it in intramembranous bone formation of the palate. Protein localization assay, transcriptional activity assay, snRNA-seq, immunofluorescence International dental journal Medium 41904889

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The T-box transcription factor Tbx15 is required for skeletal development. Mechanisms of development 95 15652702
2017 Archaic Adaptive Introgression in TBX15/WARS2. Molecular biology and evolution 93 28007980
2004 Dorsoventral patterning of the mouse coat by Tbx15. PLoS biology 85 14737183
2007 Transcriptional repression by the T-box proteins Tbx18 and Tbx15 depends on Groucho corepressors. The Journal of biological chemistry 82 17584735
2015 Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism. Nature communications 76 26299309
2012 An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes. American journal of physiology. Endocrinology and metabolism 74 22912368
2011 Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration. Proceedings of the National Academy of Sciences of the United States of America 68 21282637
2005 Genetics of shoulder girdle formation: roles of Tbx15 and aristaless-like genes. Development (Cambridge, England) 58 15728667
2008 TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome. American journal of human genetics 52 19068278
2002 Cloning of zebrafish T-box genes tbx15 and tbx18 and their expression during embryonic development. Mechanisms of development 46 12175500
2021 TBX15/miR-152/KIF2C pathway regulates breast cancer doxorubicin resistance via promoting PKM2 ubiquitination. Cancer cell international 44 34663310
2017 Tbx15 Defines a Glycolytic Subpopulation and White Adipocyte Heterogeneity. Diabetes 40 28847884
1998 Cloning, mapping, and expression analysis of TBX15, a new member of the T-Box gene family. Genomics 40 9693034
2021 CircPVT1 promotes progression in clear cell renal cell carcinoma by sponging miR-145-5p and regulating TBX15 expression. Cancer science 35 33453148
2021 Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes. Genome medicine 35 34340684
2019 Tbx15 is required for adipocyte browning induced by adrenergic signaling pathway. Molecular metabolism 27 31352005
2011 Combination of promoter hypomethylation and PDX1 overexpression leads to TBX15 decrease in vascular IUGR placentas. Epigenetics 23 20962579
2019 MiR-212-5p inhibits the malignant behavior of clear cell renal cell carcinoma cells by targeting TBX15. European review for medical and pharmacological sciences 19 31858538
2016 Promoter methylation and downregulated expression of the TBX15 gene in ovarian carcinoma. Oncology letters 19 27698863
2016 NF-κB Mediates the Expression of TBX15 in Cancer Cells. PloS one 17 27327083
2015 Novel antiapoptotic effect of TBX15: overexpression of TBX15 reduces apoptosis in cancer cells. Apoptosis : an international journal on programmed cell death 14 26216026
2010 Tbx18 and Tbx15 null-like phenotypes in mouse embryos expressing Tbx6 in somitic and lateral plate mesoderm. Developmental biology 14 20832395
2013 Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome. American journal of medical genetics. Part A 13 24039145
2020 Osteoporosis- and obesity-risk interrelationships: an epigenetic analysis of GWAS-derived SNPs at the developmental gene TBX15. Epigenetics 10 31975641
2021 The effects of Tbx15 and Pax1 on facial and other physical morphology in mice. FASEB bioAdvances 9 34938962
2023 The overexpression and clinical significance of TBX15 in human gliomas. Scientific reports 6 37328486
2021 Tbx15/18/22 shares a binding site with Tbx6-r.b to maintain expression of a muscle structural gene in ascidian late embryos. Developmental biology 6 34963554
2023 Sulforaphane Targets the TBX15/KIF2C Pathway to Repress Glycolysis and Cell Proliferation in Gastric Carcinoma Cells. Nutrition and cancer 5 37139873
2024 TBX15 facilitates malignant progression of glioma by transcriptional activation of TXDNC5. iScience 3 38327797
2024 An abdominal obesity missense variant in the adipocyte thermogenesis gene TBX15 is implicated in adaptation to cold in Finns. American journal of human genetics 3 39515300
2022 Mutations in the TBX15-ADAMTS2 pathway associate with a novel soft palate dysplasia. Human mutation 2 36124393
2021 TBX15 rs98422, DNM3 rs1011731, RAD51B rs8017304, and rs2588809 Gene Polymorphisms and Associations With Pituitary Adenoma. In vivo (Athens, Greece) 1 33622874
2026 A Novel Nonsense Variant in TBX15 Transcription Factor Suggests an Expanded Genetic Spectrum Of Submucous Cleft Palate. International dental journal 0 41904889
2025 Expanding the Clinical Spectrum of Cousin Syndrome: A Novel Biallelic Missense Variant in TBX15 Causing a Milder Phenotype. American journal of medical genetics. Part A 0 40693652

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