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The genome-wide enhancer profiling of breast cancer in the MMTV-PyVT mice [RNA-seq]

ABSTRACT: Activation of transcription enhancers, especially super enhancers, is one of the important epigenetic features of tumorigenesis. However, only very few studies reported how the enhancer landscape evolves during tumorigensis. Here we utilized a proteomics approach and found that H3K27ac and H4K8ac are elevated in the mammary tumor of MMTV-PyVT mouse model, which was then confirmed by IHC results in human BRCA chips. ChIP-seq studies revealed that H4K8ac is highly co-localized with H3K27ac on chromatin, especially on the distal enhancers . We further identified a subgroup of super enhancers which are marked by H3K4me3 peaks in the intergenic regions. These H3K4me3-enriched super enhancers are covered with higher level of H3K27ac and H4K8ac in tumor than normal tissue , and accompanies higher transcription level of the adjacent genes. Combined with global gene expression data, we identified 148 tumor H3K4me3-enriched super enhancer adjacent genes with higher expression in the tumor tissues , which may be critical for breast cancer. We further utilized one inhibitor of p300, C646, to inhibit H3K27ac level, which successfully repressed tumor formation process probably through inhibiting Vegfa and other oncogenes. Taken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer, and raises the possibility of cancer treatment through modulating enhancer activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE118802 | GEO | 2019/08/18

REPOSITORIES: GEO

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The genome-wide enhancer profiling of breast cancer in the MMTV-PyVT mice [ChIP-seq]

Project description:Activation of transcription enhancers, especially super enhancers, is one of the important epigenetic features of tumorigenesis. However, only very few studies reported how the enhancer landscape evolves during tumorigensis. Here we utilized a proteomics approach and found that H3K27ac and H4K8ac are elevated in the mammary tumor of MMTV-PyVT mouse model, which was then confirmed by IHC results in human BRCA chips. ChIP-seq studies revealed that H4K8ac is highly co-localized with H3K27ac on chromatin, especially on the distal enhancers . We further identified a subgroup of super enhancers which are marked by H3K4me3 peaks in the intergenic regions. These H3K4me3-enriched super enhancers are covered with higher level of H3K27ac and H4K8ac in tumor than normal tissue , and accompanies higher transcription level of the adjacent genes. Combined with global gene expression data, we identified 148 tumor H3K4me3-enriched super enhancer adjacent genes with higher expression in the tumor tissues , which may be critical for breast cancer. We further utilized one inhibitor of p300, C646, to inhibit H3K27ac level, which successfully repressed tumor formation process probably through inhibiting Vegfa and other oncogenes. Taken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer, and raises the possibility of cancer treatment through modulating enhancer activity.

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