Epigenetic Regulation of Human Genome Involves CTCF/BORIS-Binding Regions

Victor Lobanenkov
Section of Molecular Pathology, Laboratory of Immunopathology; National Institutes of Health

In mammals, epigenetic regulation of a chromatin region supporting differential gene expression often goes along with moving of nascent non-coding transcripts, and involves complex structure-functional interplay of DNA-methylation and interactions with MBDs, as well as alterations in nucleosomes, including posttranslational modifications of the core histones that emerged as epigenetic "histone code". Targeted recruitment of "epigenetic enzymes" - such as DNA/RNA-helicases, Lys- and Arg- specific HMTases, DNMTs, and of possible dMTases (demethylases) - also appears to be one of the necessary steps associated with region-specific chromatin remodelling. However, none of the aforementioned components of epigenetic machinery are capable of sequence-specific recognition of DNA thereby raising the question of which factors and how may mediate correct targeting of epigenetic processes to specific regions in genome to ensure that normal assembly of silenced vs. activated domains in dynamic chromatin hubs are maintained and re-established in the patterns properly coordinated in time and space. We asked if frequently observed in various cancers regional DNA-demethylation accompanied by site-specific DNA-hypermethylation might have a common mechanistic denominator associated with a common malfunction in a DNA-targeting part of the epigenetic machinery. Such targeting cannot occur without factors capable of multiple site-specific DNA recognition, but their identity remained elusive until CTCF/BORIS-binding regions have emerged as the most common places of epigenetic regulation and reprogramming. BORIS is a mammalian CTCF-paralog with the same conserved 11 Zn-fingers (11ZF) that mediate multiple site-specific interactions with varying ~50bp-long target sequences. CTCF is normally present in all somatic cells, while BORIS is normally active only in CTCF- and 5-MeC-deficient adult male germ cells, but it is also very frequently found aberrantly de-repressed in various cancers. Here we will present and discuss data showing how switching of DNA occupancy from CTCF to BORIS regulates epigenetic reprogramming in cancer, and in cultured cells treated with chromatin remodelling agents and/or methylation-inhibitors such as 5-azadC (5-aza-2'deoxycytidine), etc. For references, see back-to-back papers by Vatolin et.al. and Hong et.al. in Cancer Res. (2005), v. 65, p. 7751 - 62 and p. 7763 - 74, respectively, and literature therein.