期刊
EPIGENETICS
卷 5, 期 8, 页码 716-729出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/epi.5.8.13014
关键词
histone modifications; gene expression; chromatin remodeling; ovarian cancer; epigenetic plasticity; tumor microenvironment; bivalent histone mark
资金
- National Cancer Institute [CA113001, CA085289]
- NCCS
- Department of Biotechnology, Govt. of India
- Council of Scientific & Industrial Research, India
- Indiana University
- Andrea Caperell
- Indiana Genomics Initiative of Indiana University, INGEN
- Lilly Endowment, Inc.
Epigenetic plasticity refers to the capability of mammalian cells to alter their differentiation status via chromatin remodeling-associated alterations in gene expression. While epigenetic plasticity has been best associated with lineage commitment of embryonic stem cells, recent studies have demonstrated chromatin remodeling even in terminally differentiated normal cells and advanced-stage melanoma and breast cancer cells, in context-dependent responses to alterations in their microenvironment. In the current study, we extend this attribute of epigenetic plasticity to aggressive ovarian cancer cells, by using an integrative approach to associate cellular phenotypes with chromatin modifications (ChIP-chip) and mRNA and microRNA expression. While we identified numerous gene promoters possessing the well-known bivalent mark of H3K27me3/H3K4me2, we also report 14 distinct, lesser known bi-, tri- and tetravalent combinations of activating and repressive chromatin modifications, in platinum-resistant CP70 ovarian cancer cells. The vast majority (>90%) of all the histone marks studied localized to regions within 2,000 bp of transcription start sites, supporting a role in gene regulation. Upon a simple alteration in the microenvironment, transition from two-to three-dimensional culture, an increase (17-38%) in repressive-only marked promoters was observed, concomitant with a decrease (31-21%) in multivalent (i.e., juxtaposed permissive and repressive histone marked) promoters. Like embryonic/tissue stem and other (non-ovarian) carcinoma cells, ovarian cancer cell epigenetic plasticity reflects an inherent transcriptional flexibility for context-responsive alterations in phenotype. It is possible that this plasticity could be therapeutically exploited for the management of this lethal gynecologic malignancy.
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