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Broad H3K4me3 Reveals Increased Transcription Elongation and Enhancer Activity at Tumor Suppressors

ABSTRACT: Tumor suppressors are mostly defined by inactivating somatic mutations in tumors, yet little is known about their epigenetic features in normal cells. Here, through integrative analysis of 1,134 genome-wide epigenetic profiles and mutations from >8,200 tumor-normal pairs, we discovered broad H3K4me3 (wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity together leading to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super enhancers. Broad H3K4me3 conserved across normal cells represents core tumor suppressors, such as P53 and PTEN, whereas cell-type-specific broad H3K4me3 may indicate cell-identity genes and cell-type-specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 in cancers is strongly associated with repression of tumor suppressors. Together, the broad H3K4me3 epigenetic signature we reported here may provide a new direction for the discovery and characterization of novel tumor suppressors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67471 | GEO | 2015/07/29

SECONDARY ACCESSION(S): PRJNA279999

REPOSITORIES: GEO

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Project description:Aberrational epigenetic marks are believed to play a major role in establishing the abnormal features of cancer cells. Rational use and development of drugs aimed at epigenetic processes requires an understanding of the range, extent, and roles of epigenetic reprogramming in cancer cells. Using ChIP-chip and MeDIP-chip approaches, we localized well-established and prevalent epigenetic marks (H3K27me3, H3K4me3, H3K9me3, DNA methylation) on a genome scale in several lines of putative glioma stem cells (brain tumor stem cells, BTSCs) and, for comparison, normal human fetal neural stem cells (fNSCs). We determined a substantial M-bM-^@M-^\coreM-bM-^@M-^] set of promoters possessing each mark in every surveyed BTSC cell type, which largely overlapped the corresponding fNSC sets. However, there was substantial diversity among cell types in mark localization. We observed large differences among cell types in total number of H3K9me3+ positive promoters and peaks and in broad modification areas for H3K27me3 and, to a lesser extent, H3K9me3. We verified that a change in a broad modification (defined as >50 kb peak length) affected gene expression of CACNG7. We detected large numbers of bivalent promoters, but most bivalent promoters did not display direct overlap of contrasting epigenetic marks, but rather occupied nearby regions of the proximal promoter. There were significant differences in the sets of promoters bearing bivalent marks in the different cell types and few consistent differences between fNSCs and BTSCs. Overall, our M-bM-^@M-^\core setM-bM-^@M-^] data establishes sets of potential therapeutic targets, but the diversity in sets of sites and broad modifications among cell types underscores the need to carefully consider BTSC subtype variation in epigenetic therapy. Our results point toward substantial differences among cell types in the activity of the production/maintenance systems for H3K9me3 and for broad regions of modification (H3K27me3 or H3K9me3). Finally, the unexpected diversity in bivalent promoter sets among these multipotent cells indicates that bivalent promoters may play complex roles in the overall biology of these cells. These results provide key information for forming the basis for future rational drug therapy aimed at epigenetic processes in these cells. ChIP-chip and MeDIP-chip localization of histone modifications and DNA methylation in glioma stem cells and fetal neural stem cells comparison of 4 lines of brain tumor stem cells to each other and to normal fetal neural stem cells

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Broad H3K4me3 Reveals Increased Transcription Elongation and Enhancer Activity at Tumor Suppressors

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