Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis

Abstract

Genetic and epigenetic regulations are essential mechanisms that ensure proper early and subsequent mammalian programming of diverse cellular processes. These mechanisms affect transcriptional regulation, stem cell determination and cell cycle control, including senescence and aging. It is not surprising that perturbation of the exquisite balance between genetic and epigenetic regulation can lead to diverse diseases, including cancer. Histone covalent modifications and DNA methylation do not explain all epigenetic phenomena. We describe a previously unsuspected epigenetic factor and propose the incorporation of the 11-zinc finger CCCTC-binding factor, known as CTCF as a novel and multifunctional epigenetic regulator.

Epigenetic Regulation of the Human Retinoblastoma Tumor Suppressor Gene Promoter by CTCF

“…The most recent evidence of the protective function of CTCF against epigenetic silencing is at the DM1 locus, which is related to the myotonic dystrophy disorder. The data support a model in which CTCF restricts the production of a bidirectional intergenic transcript, histone H3-K9 methylation, incorporation of HP1g and DNA methylation, maintaining the stability of the intergenic region and normal amounts of CTG repeats (35,36).…”

“…A large amount of data exist concerning the role of CTCF at imprinted genes, in particular, its ability to maintain one of the alleles at imprinted loci unmethylated and to maintain an open chromatin conformation in genes that escape X chromosome inactivation (ICR; refs. 10, [33][34][35]. The most recent evidence of the protective function of CTCF against epigenetic silencing is at the DM1 locus, which is related to the myotonic dystrophy disorder.…”

BORIS and CTCF are overexpressed in squamous intraepithelial lesions and cervical cancer

“…CTCF overexpression has been associated with growth suppression in different cellular systems; therefore, it is considered to be a tumor suppressor (Rasko et al, 2001;Rakha et al, 2004;Torrano et al, 2005;Docquier et al, 2005;Recillas-Targa et al, 2006;Ramli et al, 2012;Ouboussad et al, 2013). However, the opposite effect has been observed in other cell types (Heath et al, 2008); thus, it has been hypothesized that these differences in gene transcription and regulation of cell growth mediated by CTCF depend on the chromatin environment, transcriptional machinery, and metabolic state of different cell types .…”

Algorithms for CpG Islands Search: New Advantages and Old Problems

“…Fan and colleagues (Fan et al, 2007) assume that all proteins with zinc-finger domain can play a role in CpG boundaries formation. Some other proteins, like VEZF1 (Dickson et al, 2010) and CTCF (Filippova et al, 2005;Recillas-Targa et al, 2006), also participate in this process. Naumann (Naumann et al, 2009) shows that loss of such a boundary (in fragile X-chromosome syndrome) leads to spread of methylation and gene inactivation.…”

“…Moreover CGIs obtaining CTCF binding sites can themselves play a role of insulators forming boundaries of chromatin domains (Filippova et al, 2005). Other DNA binding proteins with GC-rich binding sites can also decrease the level of DNA methylation (Lin et al, 2000;Recillas-Targa et al, 2006). It's most likely that unmethylated CpG islands form open chromatin structures simplifying the transcription (Choi, 2010).…”