The Structural Complexity of the Human BORIS Gene in Gametogenesis and Cancer

PLoS One

Eugene Barsov¹  Svetlana D. Pack²  Alexander A. Vostrov³  Teruhiko Suzuki⁴  Jeongheon Yoon⁴  Natsuki Kosaka-Suzuki⁴  Herbert C. Morse III⁴  Victor Lobanenkov⁴  Elena M. Pugacheva⁴  Dmitri Loukinov⁴  Alexander V. Strunnikov⁴ 

[1] AIDS and Cancer Viruses Program, SAIC-Frederick/NCI-Frederick, Frederick, Maryland, United States of America;Chromosome Pathology Unit, Laboratory of Pathology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, United States of America;Department of Psychiatry and Behavioral Science, State University of New York at Stony Brook, Stony Brook, New York, United States of America;Laboratory of Immunopathology, National Institute of Allergy and Infectious Disease, National Institutes of Health (NIH), Rockville, Maryland, United States of America

关键词: DNA methylation;    Polymerase chain reaction;    DNA-binding proteins;    DNA transcription;    Alternative splicing;    Transfection;    Small interfering RNAs;    Reverse transcriptase-polymerase chain reaction;   

DOI  :  10.1371/journal.pone.0013872

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY