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Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line

ABSTRACT: Epigenetic reprogramming is commonly observed in cancer, and is hypothesized to involve multiple mechanisms, including DNA methylation and Polycomb repressive complexes (PRCs). Here we devise a new experimental and analytical strategy using customized high density tiling arrays to investigate coordinated patterns of gene expression, DNA methylation and Polycomb marks which differentiate prostate cancer cells from their normal counterparts. Three major changes in the epigenomic landscape distinguish the two cell types. Developmentally significant genes containing CpG islands which are silenced by PRCs in the normal cells acquire DNA methylation silencing and lose their PRC marks (epigenetic switching). Since these genes are normally silent this switch does not cause de novo repression but might significantly reduce epigenetic plasticity. Two other groups of genes are silenced by either de novo DNA methylation without PRC occupancy (5mC reprogramming) or by de novo PRC occupancy without DNA methylation (PRC reprogramming). Our data suggest that the two silencing mechanisms act in parallel to reprogram the cancer epigenome, and that DNA hypermethylation may replace Polycomb based repression near key regulatory genes, possibly reducing their regulatory plasticity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE12334 | GEO | 2008/08/07

SECONDARY ACCESSION(S): PRJNA113227

REPOSITORIES: GEO

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Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line

Project description:Epigenetic reprogramming is commonly observed in cancer, and is hypothesized to involve multiple mechanisms, including DNA methylation and Polycomb repressive complexes (PRCs). Here we devise a new experimental and analytical strategy using customized high density tiling arrays to investigate coordinated patterns of gene expression, DNA methylation and Polycomb marks which differentiate prostate cancer cells from their normal counterparts. Three major changes in the epigenomic landscape distinguish the two cell types. Developmentally significant genes containing CpG islands which are silenced by PRCs in the normal cells acquire DNA methylation silencing and lose their PRC marks (epigenetic switching). Since these genes are normally silent this switch does not cause de novo repression but might significantly reduce epigenetic plasticity. Two other groups of genes are silenced by either de novo DNA methylation without PRC occupancy (5mC reprogramming) or by de novo PRC occupancy without DNA methylation (PRC reprogramming). Our data suggest that the two silencing mechanisms act in parallel to reprogram the cancer epigenome, and that DNA hypermethylation may replace Polycomb based repression near key regulatory genes, possibly reducing their regulatory plasticity. Profiling 5mC and H3K27m3/Suz12 occupancy in the PC3 cancer line and the PrEC system. Hybridization over a custom array including a representative set of promoters (-2.5 to +1 kb) with variable CpG content levels and variable expression levels in the two cell systems.

2008-08-07 | E-GEOD-12334 | biostudies-arrayexpress

EED and IgG (as control) co-immunoprecipitation of wild type embryonic stem cells (ESCs), with 3 biological replicates per condition.

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Project description:Early mammalian development is accompanied by a profound global remodeling of chromatin-based regulation. The Zdbf2 locus provides a valuable model to uncover the effect of dynamic chromatin transition, as it is polycomb silenced in embryonic stem cells (ESCs) and only becomes activated after Long isoform of Zdbf2 (Liz) transcription-dependent de novo DNA methylation during differentiation. Here we show that four enhancers contribute to the Liz-to-Zdbf2 promoter switch, concomitantly with dynamic changes in chromatin architecture. CTCF plays a key role in partitioning the locus in ESCs, when Liz is active and Zdbf2 is silenced. The partition is relieved when Zdbf2 becomes DNA methylated and active. Mutant ESCs that lack the partition fail to properly activate Zdbf2. Notably, the CTCF-based regulation occurs independently of the polycomb and DNA methylation pathways, suggesting a multi-layered regulatory framework that ensures proper epigenetic programming of a developmentally important gene.

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