The INK4B-ARF-INK4A (INK/ARF) locus is composed of three tumor suppressor genes, which are kept silenced by DNA methylation in different cancer types. In addition, a non-coding RNA (ANRIL) is transcribed in the anti-sense orientation upstream of the ARF gene. The resulting divergent promoter region is bound by the chromatin insulator protein CTCF in association with histone H3 tri-methylated on lysine 4, irrespective of transcription of ANRIL and ARF. Methylation of the overlapping CpG island abolishes CTCF binding and the associated modification, which can be restored by 5-Aza-2′-deoxycytidine (5-Aza-dC) treatment. shRNA knock down of CTCF expression dramatically reduces the induction of ANRIL and ARF, but also that of INK4A and INK4B expression by 5-Aza-dC. We propose that CTCF is an essential factor for transcription of the INK/ARF locus and that abrogation of its binding by DNA methylation contributes to the permanent silencing of several genes of the locus in tumors.
CTCF is a DNA methylation-sensitive positive regulator of the INK/ARF locus
Rodriguez, C.; Borgel, J.; Court, F.; Cathala, G.; Forne, T.; Piette, J.
Biochem Biophys Res Commun
2010-02-05 / vol 392 / pages 129-34
10.1016/j.bbrc.2009.12.159 S0006-291X(09)02557-1 [pii]
1090-2104 (Electronic) 0006-291X (Linking)
IGMM team(s) involved in this publication
Genome Organization and Epigenetic Control
Cell Line, Tumor; Humans; Transcriptional Activation; Genetic Loci; *DNA Methylation; Promoter Regions, Genetic; *Gene Expression Regulation, Neoplastic; Repressor Proteins/*metabolism; *Genes, p16; Cyclin-Dependent Kinase Inhibitor p15/*genetics; Neoplasms/*genetics; Tumor Suppressor Protein p14ARF/*genetics