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DNA Methyltransferase 1 and 3B Activate BAG-1 Expression via Recruitment of CTCFL/BORIS and Modulation of Promoter Histone Methylation

¹ Radiation Oncology Branch and ² Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and ³ Department of Medicine and Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Andrew P. Feinberg, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-614-3489; E-mail: afeinberg{at}jhu.edu or David Gius, Radiation Oncology Branch, National Cancer Institute, NIH, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-496-5457; Fax: 301-480-5439; E-mail: giusd{at}mail.nih.gov.

Key Words: BORIS • CTCF • chromatin • BAG-1 • gene expression

In a previous genomic analysis, using somatic methyltransferase (DNMT) knockout cells, we showed that hypomethylation decreased the expression of as many genes as were observed to increase, suggesting a previously unknown mechanism for epigenetic regulation. To address this idea, the expression of the BAG family genes was used as a model. These genes were used because their expression was decreased in DNMT1^–/–, DNMT3B^–/–, and double knockout cells and increased in DNMT1-overexpressing and DNMT3B-overexpressing cells. Chromatin immunoprecipitation analysis of the BAG-1 promoter in DNMT1-overexpressing or DNMT3B-overexpressing cells showed a permissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status associated with DNA-binding of CTCFL/BORIS, as well as increased BAG-1 expression. In contrast, a nonpermissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status was associated with CTCF DNA-binding and decreased BAG-1 expression in the single and double DNMT knockout cells. BORIS short hairpin RNA knockdown decreased both promoter DNA-binding, as well as BAG-1 expression, and changed the dimethyl-H3-K4/dimethyl-H3-K9 ratio to that characteristic of a nonpermissive chromatin state. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation. [Cancer Res 2008;68(8):2726–35]