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Background  Tumor suppressor gene (TSG)  RASSF1A  and candidate TSG  BLU  are two tandem head-to-tail genes located at 3p21.3. We hypothesized that there may be a concordance on their gene expression and promoter methylation status. If not, then there may be an insulator located between  RASSF1A  and  BLU  genes that provides a barrier activity.    Methodology/Principal Findings  We first identified potential transcriptionally important CpG sites using the methylation-specific oligonucleotide array in relation to mRNA expression of  RASSF1A  and  BLU  genes in primary lung tumors. We demonstrated that E2F1 bound to the potential transcriptionally important CpG sites in  RASSF1A  gene of a normal lung cell line expressing  RASSF1A  transcripts, whereas loss of E2F1 binding to  RASSF1A  in A549 cancer cell line was the result of DNA methylation. Both  RASSF1A  and  BLU  genes had their own potential transcriptionally important CpG regions. However, there was no correlation of methylation status between  RASSF1A  and  BLU . Using gel shift assay and chromatin immunoprecipitation-PCR (ChIP-PCR), we found that CCCTC-binding factor (CTCF) bound to insulator sequences located between these two genes. Bisulfite sequencing and ChIP-PCR revealed distinct methylation and chromatin boundaries separated by the CTCF binding domains in normal cells, whereas such distinct epigenetic domains were not observed in cancer cells. Note that demethylation reagent and histone deacetylase inhibitor treatments led to CTCF binding and recovery of barrier effect for  RASSF1A  and  BLU  genes in cancer cells.    Conclusions/Significance  Our study dissects the potential transcriptionally important CpG sites for  RASSF1A  and  BLU  genes at the sequence level and demonstrates that CTCF binding to the insulator of  BLU  gene provides a barrier activity within separate epigenetic domains of the juxtaposed  BLU  and  RASSF1A  loci in the 3p21.3 gene cluster region.

Distinct Epigenetic Domains Separated by a CTCF Bound Insulator between the Tandem Genes, BLU and RASSF1A