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Histone H3 lysine 4 acetylation and methylation dynamics define breast cancer subtypes

Terri L. Messier, Jonathan A. R. Gordon, Joseph R. Boyd, Coralee E. Tye, Gillian Browne, Janet L. Stein, Jane B. Lian and Gary S. Stein _

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Oncotarget. 2016; 7:5094-5109. https://doi.org/10.18632/oncotarget.6922

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Terri L. Messier1, Jonathan A. R. Gordon1, Joseph R. Boyd1, Coralee E. Tye1, Gillian Browne1, Janet L. Stein1, Jane B. Lian1 and Gary S. Stein1

1 Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA

Correspondence to:

Gary S. Stein, email:

Keywords: epigenetics, breast cancer, estrogen receptor pathway, EMT pathway, histone H3K4 modifications

Received: September 21, 2015 Accepted: January 06, 2016 Published: January 15, 2016


The onset and progression of breast cancer are linked to genetic and epigenetic changes that alter the normal programming of cells. Epigenetic modifications of DNA and histones contribute to chromatin structure that result in the activation or repression of gene expression. Several epigenetic pathways have been shown to be highly deregulated in cancer cells. Targeting specific histone modifications represents a viable strategy to prevent oncogenic transformation, tumor growth or metastasis. Methylation of histone H3 lysine 4 has been extensively studied and shown to mark genes for expression; however this residue can also be acetylated and the specific function of this alteration is less well known. To define the relative roles of histone H3 methylation (H3K4me3) and acetylation (H3K4ac) in breast cancer, we determined genomic regions enriched for both marks in normal-like (MCF10A), transformed (MCF7) and metastatic (MDA-MB-231) cells using a genome-wide ChIP-Seq approach. Our data revealed a genome-wide gain of H3K4ac associated with both early and late breast cancer cell phenotypes, while gain of H3K4me3 was predominantly associated with late stage cancer cells. Enrichment of H3K4ac was over-represented at promoters of genes associated with cancer-related phenotypic traits, such as estrogen response and epithelial-to-mesenchymal transition pathways. Our findings highlight an important role for H3K4ac in predicting epigenetic changes associated with early stages of transformation. In addition, our data provide a valuable resource for understanding epigenetic signatures that correlate with known breast cancer-associated oncogenic pathways.

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