Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells

Sharmila A. Bapat, Victor Jin, Nicholas Berry, Curt Balch, Neeti Sharma, Nawneet Kurrey, Shu Zhang, Fang Fang, Xun Lan, Meng Li, Brian Kennedy, Robert M. Bigsby, Tim HM Huang, Kenneth P. Nephew

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

"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 "ChIPchip") 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 CP 70 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.

Original languageEnglish (US)
Pages (from-to)717-730
Number of pages14
JournalEpigenetics
Volume5
Issue number8
DOIs
StatePublished - 2010
Externally publishedYes

Keywords

  • Bivalent histone mark
  • Chromatin remodeling
  • Epigenetic plasticity
  • Gene expression
  • Histone modifications
  • Ovarian cancer
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Bapat, S. A., Jin, V., Berry, N., Balch, C., Sharma, N., Kurrey, N., Zhang, S., Fang, F., Lan, X., Li, M., Kennedy, B., Bigsby, R. M., Huang, T. HM., & Nephew, K. P. (2010). Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells. Epigenetics, 5(8), 717-730. https://doi.org/10.4161/epi.5.8.13014