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The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide.

ABSTRACT: All known vertebrate chromatin insulators interact with the highly conserved, multivalent 11-zinc finger nuclear factor CTCF to demarcate expression domains by blocking enhancer or silencer signals in a position-dependent manner. Recent observations document that the properties of CTCF include reading and propagating the epigenetic state of the differentially methylated H19 imprinting control region. To assess whether these findings may reflect a universal role for CTCF targets, we identified more than 200 new CTCF target sites by generating DNA microarrays of clones derived from chromatin-immunopurified (ChIP) DNA followed by ChIP-on-chip hybridization analysis. Target sites include not only known loci involved in multiple cellular functions, such as metabolism, neurogenesis, growth, apoptosis, and signalling, but potentially also heterochromatic sequences. Using a novel insulator trapping assay, we also show that the majority of these targets manifest insulator functions with a continuous distribution of stringency. As these targets are generally DNA methylation-free as determined by antibodies against 5-methylcytidine and a methyl-binding protein (MBD2), a CTCF-based network correlates with genome-wide epigenetic states.

SUBMITTER: Mukhopadhyay R

PROVIDER: S-EPMC509268 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide.

Mukhopadhyay Rituparna R Yu WenQiang W Whitehead Joanne J Xu JunWang J Lezcano Magda M Pack Svetlana S Kanduri Chandrasekhar C Kanduri Meena M Ginjala Vasudeva V Vostrov Alexander A Quitschke Wolfgang W Chernukhin Igor I Klenova Elena E Lobanenkov Victor V Ohlsson Rolf R

Genome research 20040715 8

All known vertebrate chromatin insulators interact with the highly conserved, multivalent 11-zinc finger nuclear factor CTCF to demarcate expression domains by blocking enhancer or silencer signals in a position-dependent manner. Recent observations document that the properties of CTCF include reading and propagating the epigenetic state of the differentially methylated H19 imprinting control region. To assess whether these findings may reflect a universal role for CTCF targets, we identified mo ...[more]

PMID: 15256511

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Project description:Epstein-Barr virus (EBV) is associated with 10% of human gastric carcinomas, which are distinguished by a CpG island methylator phenotype. In gastric carcinoma tumors and cell lines, the EBV genome also exhibits a high degree of 5-methyl cytosine (5mC) marks, which are propagated by host DNA methyltransferases (DNMT) with each cell cycle. Therefore, we sought to determine the effect of DNMT inhibition by the small molecule Decitabine (DCB) on EBV genomic 5mC and chromatin structure in two tumor-derived gastric cancer cell lines, YCCEL1 and SNU719. Decitabine effects on EBV genomic 5mC, chromatin structure, and viral gene expression were profiled by reduced representation bisulfite sequencing, ATAC-seq, and RNA-seq, respectively. Decitabine treatment resulted in global viral genome hypomethylation and a global increase in open chromatin. The most striking finding resulted from analyzing the methylation pattern from single RRBS sequencing reads, showing that the EBV genome contains a heterogeneous pool of epigenetic states, each of which is eroded upon Decitabine treatment. We observed heterogeneous 5mC epiallele patterns around EBV genomic CTCF binding sites and lytic gene transcriptional start sites. These results highlight the importance of 5mC in maintaining EBV genomic chromatin structure and latency. Furthermore, the presence of 5mC epialleles suggests EBV+ gastric cancers harbor transcriptionally distinct EBV episomes, which may exert distinct functional roles in maintaining latency and driving tumorigenesis. IMPORTANCE Epstein-Barr virus (EBV) latency is controlled by epigenetic silencing by DNA methylation [5-methyl cytosine (5mC)], histone modifications, and chromatin looping. However, how they dictate the transcriptional program in EBV-associated gastric cancers remains incompletely understood. EBV-associated gastric cancer displays a 5mC hypermethylated phenotype. A potential treatment for this cancer subtype is the DNA hypomethylating agent, which induces EBV lytic reactivation and targets hypermethylation of the cellular DNA. In this study, we identified a heterogeneous pool of EBV epialleles within two tumor-derived gastric cancer cell lines that are disrupted with a hypomethylating agent. Stochastic DNA methylation patterning at critical regulatory regions may be an underlying mechanism for spontaneous reactivation. Our results highlight the critical role of epigenetic modulation on EBV latency and life cycle, which is maintained through the interaction between 5mC and the host protein CCCTC-binding factor.

Dataset Information

The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide.

Publications

The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide.

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