Expression of a Testis-Specific Form of Gal3st1 (CST), a Gene Essential for Spermatogenesis, Is Regulated by the CTCF Paralogous Gene BORIS

Laboratory of Immunopathology, National Institutes of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 03/2010; 30(10):2473-84. DOI: 10.1128/MCB.01093-09
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Previously, it was shown that the CTCF paralogous gene, BORIS (brother of the regulator of imprinted sites) is expressed in male germ cells, but its function in spermatogenesis has not
been defined. To develop an understanding of the functional activities of BORIS, we generated BORIS knockout (KO) mice. Mice homozygous for the null allele had a defect in spermatogenesis that resulted in small testes associated
with increased cell death. The defect was evident as early as postnatal day 21 and was manifested by delayed production of
haploid cells. By gene expression profiling, we found that transcript levels for Gal3st1 (also known as cerebroside sulfotransferase
[CST]), known to play a crucial role in meiosis, were dramatically reduced in BORIS KO testes. We found that CST is expressed in testis as a novel testis-specific isoform, CST form FTS, that has a short exon 1f. We showed that BORIS bound to and activated the promoter of CST form FTS. Mutation of the BORIS binding site in the promoter reduced the ability of BORIS to activate the promoter. These findings
define transcriptional regulation of CST expression as a critical role for BORIS in spermatogenesis.

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Available from: Herbert C Morse, Oct 05, 2015
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    • "Our results are in agreement with literature data showing that BORIS positively regulates gene expression by inducing an open chromatin conformation [41] [42] [43] [44]. BORIS induced alterations in the NOTCH3 promoter appear highly similar to those common features typical of permissive/active chromatin conformation, which have recently been reported for Gal3st1 [43], in the physiological context of spermatogenesis, and for the activation of cancer testis antigen TSP50 [39]. To note, genome-wide analyses revealed that BORIS co-localizes with H3K4me3 and active PolII Fig. 5. BORIS stimulates the activity of proximal NOTCH3 promoter. "
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    ABSTRACT: Aberrant up-regulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its up-regulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell Acute Lymphoblastic Leukaemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumours overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 06/2014; 1839(9). DOI:10.1016/j.bbagrm.2014.06.017 · 6.33 Impact Factor
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    • "The role of BORIS in chromatin activation has also been demonstrated for MAGEA1-A4 and BAG-1 genes [7], [8]. While the role of BORIS in the regulation of gene expression was demonstrated primarily for CTAs [9], [10], [11], [12], [13], its role on non-CTA genes is limited. Recent reports suggest that BORIS may bind and affect expression of MYC, BRCA1, OCT4, hTERT, and Rb2/p130, as well as the H19 imprinting control region [4], [14], [15], [16]. "
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    ABSTRACT: Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS), resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.
    PLoS ONE 07/2012; 7(7):e40389. DOI:10.1371/journal.pone.0040389 · 3.23 Impact Factor
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    • "More recently, it has been detected in human oocytes, ovary, embryonic stem cells [14] and various foetal tissues [15]. Consistent with its significant level of expression in testis, BORIS knock-out mice suffer from spermatogenesis defects that result in small testes [16]. In addition, BORIS is aberrantly expressed in many tumours [17], [18], [19] and was thus defined within the cancer-testis group of genes [10]. "
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    ABSTRACT: 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.
    PLoS ONE 06/2012; 7(6):e39371. DOI:10.1371/journal.pone.0039371 · 3.23 Impact Factor
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