Human BORIS (stands for the "Brother Of the Regulator of Imprinted Sites") is a unique cancer/testis (CTA) gene at 20q13-locus of gain/amplification observed in majority of human cancers; BORIS is a unique CTA gene because unlike other CTA genes (like MAGEs, LAGEs, NY-ISO-I, etc.) it has a somatic counterpart, called CTCF, which shares with BORIS exactly the same exons encoding for the 11 Zn-finger DNA-binding domain. BORIS is a paralogue of highly conserved from Drosophila to birds to mice to man CTCF gene that in mammalian somatic cells universally performs functional "reading" of the parent-of-origin-specific mono-allelic imprinting marks. There is no BORIS gene in chickens, etc., because it has evolved only in early placental mammals for targeting the precise resetting of epigenetic imprinting marks at CpG-methylation-sensitive CTCF-binding sequences. Such resetting of the imprints obviously requires the displacement of CTCF from DNA by a different factor that could nevertheless precisely target these same DNA sequences to undergo re-methylation during spermatogenesis. The latter would be impossible to achieve if CTCF permanently seats bound to these sequences protecting them from the easure of both maternal and paternal methylation marks by DNMT/HMTase complexes which must generate only the paternal marks at the same CTCF-sites in mature sperm. Both BORIS & CTCF share the identical DNA-binding domain of 11 identical Zn-fingers, but these two nuclear factors have no other homologies at the N- and C-termini; BORIS is normally expressed only in CTCF-negative and demethylated male germ cells during resetting of paternal gene-imprinting methylation marks. Aberrant derepresssion of BORIS in somatic cells is an oncogenic event resulting from competition with CTCF for the shared target DNA sequences (in MYC, in IGF2/H19, p16 and p19/ARF promoters, etc. CTCF has characteristics of the tumor-suppressor gene that was mapped at the 16q22 SRO for frequent LOH in various cancers. However, functional XG+F-mutations in one CTCF alleles in tumors with 16q22 LOH is a rare even because aberrant expression of BORIS palys the role of an interfering mutant if CTCF and is a much more frequent event in human cancers.
NCBI Summary:
CCCTC-binding factor (CTCF), an 11-zinc-finger factor involved in gene regulation, utilizes different zinc fingers to bind varying DNA target sites. CTCF forms methylation-sensitive insulators that regulate X-chromosome inactivation. This gene is a paralog of CTCF and appears to be expressed primarily in the cytoplasm of spermatocytes, unlike CTCF which is expressed primarily in the nucleus of somatic cells. CTCF and the protein encoded by this gene are normally expressed in a mutually exclusive pattern that correlates with resetting of methylation marks during male germ cell differentiation. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]
General function
Cell cycle regulation, Oncogenesis, DNA binding, Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Germ cell development, Early embryo development
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A cell cycle role for the epigenetic factor CTCF-L/BORIS. Rosa-Garrido M et al. CTCF is a ubiquitous epigenetic regulator that has been proposed as a master keeper of chromatin organisation. CTCF-like, or BORIS, is thought to antagonise CTCF and has been found in normal testis, ovary and a large variety of tumour cells. The cellular function of BORIS remains intriguing although it might be involved in developmental reprogramming of gene expression patterns. We here unravel the expression of CTCF and BORIS proteins throughout human epidermis. While CTCF is widely distributed within the nucleus, BORIS is confined to the nucleolus and other euchromatin domains. Nascent RNA experiments in primary keratinocytes revealed that endogenous BORIS is present in active transcription sites. Interestingly, BORIS also localises to interphase centrosomes suggesting a role in the cell cycle. Blocking the cell cycle at S phase or mitosis, or causing DNA damage, produced a striking accumulation of BORIS. Consistently, ectopic expression of wild type or GFP- BORIS provoked a higher rate of S phase cells as well as genomic instability by mitosis failure. Furthermore, down-regulation of endogenous BORIS by specific shRNAs inhibited both RNA transcription and cell cycle progression. The results altogether suggest a role for BORIS in coordinating S phase events with mitosis.
Differential expression of the embryo/cancer gene ECSA(DPPA2), the cancer/testis gene BORIS and the pluripotency structural gene OCT4, in human preimplantation development. Monk M et al. In this paper, we examine the expression profiles of two new putative pluripotent stem cell genes, the embryo/cancer sequence A gene (ECSA) and the cancer/testis gene Brother Of the Regulator of Imprinted Sites (BORIS), in human oocytes, preimplantation embryos, primordial germ cells (PGCs) and embryo stem (ES) cells. Their expression profiles are compared with that of the well-known pluripotency gene, OCT4, using a primer design that avoids amplification of the multiple OCT4 pseudogenes. As expected, OCT4 is high in human oocytes, down-regulated in early cleavage stages and then expressed de novo in human blastocysts and PGCs. BORIS and ECSA show distinct profiles of expression in that BORIS is predominantly expressed in the early stages of preimplantation development, in oocytes and 4-cell embryos, whereas ECSA is predominantly expressed in the later stages, blastocysts and PGCs. BORIS is not detected in blastocysts, PGCs or other fetal and adult somatic tissue tested. Thus, BORIS and ECSA may be involved in two different aspects of reprogramming in development, viz., in late gametogenesis, and at the time of formation of the ES cells (inner cell mass (ICM) and PGC), respectively. However, in human ES cells, where a deprogrammed stem cell state is stably established in culture, an immunofluoresence study shows that all three genes are co-expressed at the protein level. Thus, following their derivation from ICM cells, ES cells may undergo further transformation in culture to express a number of embryo and germ line stem cell functions, which, in normal development, show different temporal and spatial specificity of expression.
Expression regulated by
DNA-methylation
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Ovarian localization
Ovarian tumor
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BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer. Link PA et al. Cancer germline (CG) genes are normally expressed in germ cells and aberrantly expressed in a variety of cancers; their immunogenicity has led to the widespread development of cancer vaccines targeting these antigens. BORIS/CTCFL is an autosomal CG antigen and promising cancer vaccine target. BORIS is the only known paralog of CTCF, a gene intimately involved in genomic imprinting, chromatin insulation, and nuclear regulation. We have previously shown that BORIS is expressed in epithelial ovarian cancer (EOC) and that its expression coincides with promoter and global DNA hypomethylation. Recently, 23 different BORIS mRNA variants have been described, and have been functionally grouped into six BORIS isoform families (sf1-sf6). In the present study, we have characterized the expression of BORIS isoform families in normal ovary (NO) and EOC, the latter of which were selected to include two groups with widely varying global DNA methylation status. We find selective expression of BORIS isoform families in NO, which becomes altered in EOC, primarily by the activation of BORIS sf1 in EOC. When comparing EOC samples based on methylation status, we find that BORIS sf1 and sf2 isoform families are selectively activated in globally hypomethylated tumors. In contrast, CTCF is downregulated in EOC, and the ratio of BORIS sf1, sf2, and sf6 isoform families as a function of CTCF is elevated in hypomethylated tumors. Finally, the expression of all BORIS isoform families was induced to varying extents by epigenetic modulatory drugs in EOC cell lines, particularly when DNMT and HDAC inhibitors were used in combination.