CTCF is a DNA methylation-sensitive positive regulator of the INK/ARF locus

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• 作者：Carmen Rodriguez ; Julie Borgel ; Frank Court ; Guy Cathala ; Thierry Forné ; Jacques Piette
• 关键词：DNA methylation ; CTCF ; Tumor suppressor ; ANRIL ; ARF
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2010
• 出版时间：5 February 2010
• 年：2010
• 卷：392
• 期：2
• 页码：129-134
• 全文大小：572 K

文摘

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.