CTCF is a DNA methylation-sensitive positive regulator of the INK/ARF locus.
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.
Rodriguez
Carmen
C
Institut de Recherche en Cancérologie de Montpellier (INSERM-Université de Montpellier I U896), CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier-Cedex 5, France.
Borgel
Julie
J
Court
Frank
F
Cathala
Guy
G
Forné
Thierry
T
Piette
Jacques
J
D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D056426:Genetic Loci; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D015533:Transcriptional Activation; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF