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Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies.

ABSTRACT: CTCF (CCCTC-binding factor) is a transcription regulator with hundreds of binding sites in the human genome. It has a main function as an insulator protein, defining together with cohesins the boundaries of areas of the genome called topologically associating domains (TADs). TADs contain regulatory elements such as enhancers which function as regulators of the transcription of genes inside the boundaries of the TAD while they are restricted from regulating genes outside these boundaries. This paper will examine the most common genetic lesions of CTCF as well as its related protein CTCFL (CTCF-like also called BORIS) in cancer using publicly available data from published genomic studies. Cancer types where abnormalities in the two genes are more common will be examined for possible associations with underlying repair defects or other prevalent genetic lesions. The putative functional effects in CTCF and CTCFL lesions will also be explored.

SUBMITTER: Voutsadakis IA

PROVIDER: S-EPMC6306835 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies.

Voutsadakis Ioannis A IA

High-throughput 20181001 4

CTCF (CCCTC-binding factor) is a transcription regulator with hundreds of binding sites in the human genome. It has a main function as an insulator protein, defining together with cohesins the boundaries of areas of the genome called topologically associating domains (TADs). TADs contain regulatory elements such as enhancers which function as regulators of the transcription of genes inside the boundaries of the TAD while they are restricted from regulating genes outside these boundaries. This pa ...[more]

PMID: 30275357

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The evolution of epigenetic regulators CTCF and BORIS/CTCFL in amniotes.

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BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours.

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Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation.

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BORIS/CTCFL is an RNA-binding protein that associates with polysomes.

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| S-EPMC4219345 | biostudies-literature

BORIS/CTCFL epigenetically reprograms clustered CTCF binding sites into alternative transcriptional start sites.

Project description:Pervasive usage of alternative promoters leads to deregulation of gene expression in carcinogenesis and may drive the emergence of new genes in spermatogenesis. However, little is known regarding the mechanisms underpinning the activation of alternative promoters. In our present study, we uncovered a novel mechanism by which alternative cancer-testis-specific transcription is activated from the intergenic and intronic clustered CTCF binding sites, which are transcriptionally inert in normal somatic cells. BORIS/CTCFL, a paralog of CTCF with cancer-testis-specific expression forms a heterodimer with CTCF at the clustered binding sites thus triggering epigenetic reprogramming of these sites into units of active transcription. BORIS binding to CTCF sites leads to the recruitment of chromatin-remodeling factor SRCAP, with subsequent replacement of H2A histone with H2A.Z, therefore creating a more relaxed chromatin state in the nucleosomes flanking the clustered binding sites. This facilitates opening of chromatin beyond CTCF/BORIS binding sites and paves the way to the recruitment of multiple additional transcription factors, thereby activating transcription from a given binding site. We demonstrate that the CTCF binding sites, epigenetically reprogrammed by ectopic BORIS expression can drive the expression of cancer-testis genes, long-noncoding RNAs, retro-pseudogenes, and dormant transposable elements harbored by activated long transcripts. Taking together, our results reveal that BORIS functions as a transcription factor that epigenetically reprograms clustered CTCF binding sites into transcriptional start sites, promoting transcription from alternative promoters in both germ cells and cancer cells.

2024-01-03 | GSE207058 | GEO

The epigenetic factor BORIS (CTCFL) controls the androgen receptor regulatory network in ovarian cancer.

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BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cells.

Project description:Melanoma is among the most aggressive cancers due to its tendency to metastasize early. Phenotype switching between a proliferative and an invasive state has been suggested as a critical process for metastasis, though the mechanisms that regulate state transitions are complex and remain poorly understood. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcriptional modulator that becomes aberrantly expressed in melanoma. Yet, the role of BORIS in melanoma remains elusive. Here, we show that BORIS is involved in melanoma phenotype switching. Genetic modification of BORIS expression in melanoma cells combined with whole-transcriptome analysis indicated that BORIS expression contributes to an invasion-associated transcriptome. In line with these findings, inducible BORIS overexpression in melanoma cells reduced proliferation and increased migration and invasion, demonstrating that the transcriptional switch is accompanied by a phenotypic switch. Mechanistically, we reveal that BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition towards an invasive state, which coincided with increased expression of TGFB1. Overall, our study indicates a pro-invasive role for BORIS in melanoma via transcriptional reprogramming.

| S-EPMC7026120 | biostudies-literature

BORIS (CTCFL) is not expressed in most human breast cell lines and high grade breast carcinomas.

Project description:BORIS (CTCFL) is the only known paralog of the versatile regulatory protein CTCF, a multifunctional DNA binding protein that mediates distinct gene regulatory functions involved in cell growth, differentiation, and apoptosis. Unlike CTCF, the expression of BORIS is normally restricted to specific cells in testes (the only cells where CTCF is not expressed), where it may play a role in reprogramming the methylation pattern of male germ line DNA. Frequent amplification of the 20q13.2 region, which contains the BORIS gene, and expression of BORIS transcripts in diverse human tumors and cell lines have led to the hypothesis that aberrant expression of BORIS may play a role in tumorigenesis by interfering with CTCF functions. However, recent studies using more quantitative methods indicate low frequency of BORIS expression in melanoma, ovarian, prostate, and bladder carcinomas. To investigate the relationship between chromosome 20q13 amplification and BORIS mRNA levels within breast cancer cell lines and tissues, we developed a quantitative RT-PCR assay to measure the levels of BORIS mRNA. Endpoint RT-PCR assays were also used to investigate the possible expression of alternatively spliced variants. Using multiple primer sets and controls, we found that neither mature BORIS transcripts nor spliced variants are commonly expressed at detectable levels in malignant breast cells or tissues, although endogenous BORIS transcripts can be induced in MCF-7 cells following 5-aza-2'-deoxycytidine treatment. In conclusion, in most breast cancer cells, endogenous BORIS is unlikely to be expressed at sufficient levels to interfere with CTCF functions. Thus it is improbable that aberrant BORIS expression plays a role in most human breast cancers.

| S-EPMC2840027 | biostudies-literature

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