Expression of the CTCF-paralogous cancer-testis gene, brother of the regulator of imprinted sites (BORIS), is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors
Open Access
- 25 October 2007
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 35 (21), 7372-7388
- https://doi.org/10.1093/nar/gkm896
Abstract
BORIS , like other members of the ‘cancer/testis antigen’ family, is normally expressed in testicular germ cells and repressed in somatic cells, but is aberrantly activated in cancers. To understand regulatory mechanisms governing human BORIS expression, we characterized its 5′-flanking region. Using 5′ RACE, we identified three promoters, designated A, B and C, corresponding to transcription start sites at −1447, −899 and −658 bp upstream of the first ATG. Alternative promoter usage generated at least five alternatively spliced BORIS mRNAs with different half-lives determined by varying 5′-UTRs. In normal testis, BORIS is transcribed from all three promoters, but 84% of the 30 cancer cell lines tested used only promoter(s) A and/or C while the others utilized primarily promoters B and C. The differences in promoter usage between normal and cancer cells suggested that they were subject to differential regulation. We found that DNA methylation and functional p53 contributes to the negative regulation of each promoter. Moreover, reduction of CTCF in normally BORIS-negative human fibroblasts resulted in derepression of BORIS promoters. These results provide a mechanistic basis for understanding cancer-related associations between haploinsufficiency of CTCF and BORIS derepression, and between the lack of functional p53 and aberrant activation of BORIS .Keywords
This publication has 62 references indexed in Scilit:
- The Testis-Specific Factor CTCFL Cooperates with the Protein Methyltransferase PRMT7 in H19 Imprinting Control Region MethylationPLoS Biology, 2006
- Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesisJournal of Cellular and Molecular Medicine, 2006
- Cloning and characterization of zebrafish CTCF: Developmental expression patterns, regulation of the promoter region, and evolutionary aspects of gene organizationGene, 2006
- Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis GenesCancer Research, 2005
- CTCF is conserved from Drosophila to humans and confers enhancer blocking of the Fab‐8 insulatorEMBO Reports, 2005
- The many roles of the transcriptional regulator CTCFBiochemistry and Cell Biology, 2003
- The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancerSeminars in Cancer Biology, 2002
- BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the somaProceedings of the National Academy of Sciences, 2002
- CTCF is a uniquely versatile transcription regulator linked to epigenetics and diseaseTrends in Genetics, 2001
- Annals of Human Genetics