Transcriptional regulation of human T-box 5 gene (TBX5) by bone- and cardiac-related transcription factors

Gene. 2021 Feb 5:768:145322. doi: 10.1016/j.gene.2020.145322. Epub 2020 Nov 19.


T-box 5 (TBX5) protein belongs to the T-box family whose members play a crucial role in cell-type specification, morphogenesis and organogenesis. TBX5 is a transcription factor important for cardiac development and upper limbs formation and its haploinsufficiency causes Holt-Oram syndrome (HOS). An increase in TBX5 dosage also leads to HOS, suggesting that TBX5 is a dose-sensitive transcription factor that needs to be tightly regulated but the molecular mechanisms involved remain unclear. In this work we report the cloning and functional analysis of human TBX5 promoter region 1 (upstream of exon 1) and promoter region 2 (upstream of exon 2), that probably regulate the transcription of the different transcript variants. In silico analysis showed several binding sites for cardiac and skeletal related transcription factors (TFs) and their functionality was assessed using promoter-luciferase constructions and TF-expressing vectors. MEF2A (Myocyte enhancer factor 2 A) was shown to positively regulate both TBX5 promoters, while EGR1 (early growth response 1) repressed both promoters. SOX9 (SRY (sex determining region Y)-box 9) repressed only the activity of promoter region 2. Interestingly, YY1 (Yin and yang 1) repressed promoter region 1 (that regulates the expression of variant 1 and 3), but activated promoter region 2 (that regulates the expression of variant 4). In conclusion, this work provides novel insights toward the better understanding of TBX5 transcriptional regulation by cardiac- and skeletal-related TFs.

Keywords: Early growth response 1 (EGR1); Holt-Oram syndrome; Myocyte enhancer factor 2 A (MEF2A); SRY (sex determining region Y)-box 9 (SOX9); TBX5; Transcription regulation; Yin and yang 1 (YY1).

MeSH terms

  • Binding Sites
  • Bone and Bones / metabolism
  • Cloning, Molecular / methods*
  • Computer Simulation
  • Early Growth Response Protein 1 / metabolism
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • MEF2 Transcription Factors / metabolism
  • Myocardium / metabolism
  • Promoter Regions, Genetic
  • SOX9 Transcription Factor / metabolism
  • T-Box Domain Proteins / chemistry
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism*
  • Transcription Factors / metabolism*


  • EGR1 protein, human
  • Early Growth Response Protein 1
  • MEF2 Transcription Factors
  • MEF2A protein, human
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Transcription Factors