Abstract
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 FindingsHere 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.ConclusionsThe 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.
Highlights
BORIS (Brother Of the Regulator of Imprinted Sites) is a paralog of the multifunctional CTCF gene, which is involved in reading epigenetic marks, transcriptional gene activation and repression, X-chromosome inactivation, chromatin loop formation through dimerization and in global three-dimensional genome organization [1,2,3,4,5]
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
We previously demonstrated that expression of BORIS is restricted to testis tissues and cancer cells, with expression dependent on the CpG methylation status of alternative BORIS promoters [8,16]
Summary
BORIS (Brother Of the Regulator of Imprinted Sites) is a paralog of the multifunctional CTCF gene, which is involved in reading epigenetic marks, transcriptional gene activation and repression, X-chromosome inactivation, chromatin loop formation through dimerization and in global three-dimensional genome organization [1,2,3,4,5]. The two paralogous genes show mutually exclusive expression patterns: BORIS mRNA is abundant in male germ cells, in primary spermatocytes and round spermatids, where CTCF, which is expressed ubiquitously in somatic cells, is repressed [2]. BORIS acts as transcriptional activator of multiple testis-specific target genes during spermatogenesis, while CTCF suppresses the same targets in somatic cells [7,8,9]. While recent studies demonstrated that BORIS is a transcriptional activator of testis-specific genes, little is generally known about its biological and molecular functions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
