Document Detail


Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells.
MedLine Citation:
PMID:  20676026     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
"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 2000 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% to 38%) in repressive-only marked promoters was observed, concomitant with a decrease (31% to 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.
Authors:
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 H M Huang; Kenneth P Nephew
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-01
Journal Detail:
Title:  Epigenetics : official journal of the DNA Methylation Society     Volume:  5     ISSN:  1559-2308     ISO Abbreviation:  Epigenetics     Publication Date:    2010 Nov-Dec
Date Detail:
Created Date:  2010-12-02     Completed Date:  2011-03-09     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101265293     Medline TA:  Epigenetics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  716-29     Citation Subset:  IM    
Affiliation:
National Centre for Cell Science, NCCS Complex, Pune University Campus, Pune, India. sabapat@nccs.res.in
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MeSH Terms
Descriptor/Qualifier:
Chromatin Assembly and Disassembly*
Drug Resistance, Neoplasm*
Epigenesis, Genetic*
Female
Gene Expression Regulation, Neoplastic*
Histones / genetics,  metabolism
Humans
Neoplasm Proteins / genetics,  metabolism
Ovarian Neoplasms / genetics,  metabolism*
Promoter Regions, Genetic / genetics
Transcription, Genetic / genetics
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA085289/CA/NCI NIH HHS; CA113001/CA/NCI NIH HHS; R01 CA085289-09/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Histones; 0/Neoplasm Proteins
Comments/Corrections

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