The structural complexity of the human BORIS gene in gametogenesis and cancer

PLoS One. 2010 Nov 8;5(11):e13872. doi: 10.1371/journal.pone.0013872.


Background: BORIS/CTCFL is a paralogue of CTCF, the major epigenetic regulator of vertebrate genomes. BORIS is normally expressed only in germ cells but is aberrantly activated in numerous cancers. While recent studies demonstrated that BORIS is a transcriptional activator of testis-specific genes, little is generally known about its biological and molecular functions.

Methodology/principal findings: Here we show that BORIS is expressed as 23 isoforms in germline and cancer cells. The isoforms are comprised of alternative N- and C-termini combined with varying numbers of zinc fingers (ZF) in the DNA binding domain. The patterns of BORIS isoform expression are distinct in germ and cancer cells. Isoform expression is activated by downregulation of CTCF, upregulated by reduction in CpG methylation caused by inactivation of DNMT1 or DNMT3b, and repressed by activation of p53. Studies of ectopically expressed isoforms showed that all are translated and localized to the nucleus. Using the testis-specific cerebroside sulfotransferase (CST) promoter and the IGF2/H19 imprinting control region (ICR), it was shown that binding of BORIS isoforms to DNA targets in vitro is methylation-sensitive and depends on the number and specific composition of ZF. The ability to bind target DNA and the presence of a specific long amino terminus (N258) in different isoforms are necessary and sufficient to activate CST transcription. Comparative sequence analyses revealed an evolutionary burst in mammals with strong conservation of BORIS isoproteins among primates.

Conclusions: The extensive repertoire of spliced BORIS variants in humans that confer distinct DNA binding and transcriptional activation properties, and their differential patterns of expression among germ cells and neoplastic cells suggest that the gene is involved in a range of functionally important aspects of both normal gametogenesis and cancer development. In addition, a burst in isoform diversification may be evolutionarily tied to unique aspects of primate speciation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CCCTC-Binding Factor
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Gametogenesis / genetics*
  • Gene Expression Regulation
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • K562 Cells
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Promoter Regions, Genetic / genetics*
  • Protein Isoforms / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Testis / cytology
  • Testis / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Zinc Fingers


  • CCCTC-Binding Factor
  • CTCF protein, human
  • CTCFL protein, human
  • DNA-Binding Proteins
  • Luminescent Proteins
  • Protein Isoforms
  • Repressor Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53