Genome-wide H3K9 Histone Acetylation Profiles Are Altered in Benzopyrene-treated MCF7 Breast Cancer Cells

Abstract

Current toxicogenomic approaches generate transcriptional profiles that can identify functional gene expression signatures of environmental toxicants. However, the intricate processes governing transcription are overlaid with a complex set of molecular instructions involving epigenetic modifications. These commands regulate both gene expression and chromatin organization through coordinated sets of histone modifications and heritable DNA methylation patterns. Although the effects of specific environmental toxicants on gene expression are the subject of much study, the epigenetic effects of such compounds are poorly understood. Here we have used human promoter tiling arrays along with chromatin immunoprecipitation to identify changes in histone acetylation profiles because of chemical exposure. Chromatin from cells exposed to the polyaromatic hydrocarbon benzo(a)pyrene was immunoprecipitated with antibodies against acetylated histones. Affymetrix promoter tiling microarrays were probed to generate epigenomic profiles of hypo-and hyperacetylated chromatin localized to gene promoter regions. Statistical analyses, data mining, and expression studies revealed that treated cells possessed differentially acetylated gene promoter regions and gene-specific expression changes. This chromatin immunoprecipitation-onchip approach permits genome-wide profiling of histone acetylation patterns that can identify chromatin-related signatures of environmental toxicants and potentially determine the molecular pathways these changes target. This approach also has potential applications for profiling histone modifications and DNA methylation changes during embryonic development, in cancer biology, and in the development and assessment of cancer therapeutics.

Metformin targets histone acetylation in cancer-prone epithelial cells

“…1, middle). Because phosphorylation of H3 is clearly associated with H3 acetylation, strongly implicating a synergistic coupling of these modifications in transcription activation and the DNA damage response, [53][54][55] we explored whether H3S10 and H3T11 phosphorylation was significantly altered in BRCA1 haploinsufficient cells. BRCA1 one-hit cells likewise exhibited significantly higher levels of H3 phosphorylation on S10 and T11, which were markedly reduced by metformin (Fig.…”

New clinical and experimental approaches for studying tumor dormancy: does tumor dormancy offer a therapeutic target?

“…One strategy might be to establish epigenetic profiles related to the acquisition of dormancy as well as those related to the reversion back to a tumorigenic state. For example, whole-genome approaches comparing epigenetic profiles of primary tumors with those profiles generated from cells reappearing at a secondary site may identify unique epigenetic changes at gene targets related to the dormancy phenotype (103). Second, the responsive nature of tumor cells raises the potential to reprogram these cells by altering their secondary growth environment.…”

Chromatin Memory in the Development of Human Cancers

“…H3K27me3 seems to occur mutually exclusive to DNA methylation and promote de novo silencing of genes in different cancers [112,113] with a few exceptions [114]. Many genes that are silenced by H3K27me3 in embryonic stem cells are found silenced by DNA methylation in cancer cells, establishing an epigenetic switch from a differentiated state to a "stem cell like" signature of cancer cells.…”

“…Metal and metalloid toxicants nickel (Ni), arsenic (As), and hexavalent chromium (CrVI) can cause global post-translational histone modification level change, as well as histone mark localization alteration [112]. For example, H3K9me2, a mark of transcriptional repression; and H3K4me3, a mark of transcriptional activation, were found increased in the promoter regions of several genes involved in the transcription of DNA into RNA and the synthesis of immune response cytokines [112]. Environmentally relevant solar ultraviolet A radiation (UVA) doses (1×20 or 4×5 J cm −2 per week) cause tumorigenic conversions of HaCaT skin keratinocytes after long-term exposure (10-15 weeks) [127].…”