Document Detail

Hypoxia alters the epigenetic profile in cultured human placental trophoblasts.
MedLine Citation:
PMID:  23314690     Owner:  NLM     Status:  MEDLINE    
The mechanisms by which the placenta adapts to exogenous stimuli to create a stable and healthy environment for the growing fetus are not well known. Low oxygen tension influences placental function, and is associated with preeclampsia, a condition displaying altered development of placental trophoblast. We hypothesized that oxygen tension affects villous trophoblast by modulation of gene expression through DNA methylation. We used the Infinium HumanMethylation450 BeadChip array to compare the DNA methylation profile of primary cultures of human cytotrophoblasts and syncytiotrophoblasts under < 1%, 8% and 20% oxygen levels. We found no effect of oxygen tension on average DNA methylation for either cell phenotype, but a set of loci became hypermethylated in cytotrophoblasts exposed for 24 h to < 1% oxygen, as compared with those exposed to 8% or 20% oxygen. Hypermethylation with low oxygen tension was independently confirmed by bisulfite-pyrosequencing in a subset of functionally relevant genes including CD59, CFB, GRAM3 and ZNF217. Intriguingly, 70 out of the 147 CpGs that became hypermethylated in < 1% oxygen overlapped with CpG sites that became hypomethylated upon differentiation of cytotrophoblasts into syncytiotrophoblasts. Furthermore, the preponderance of altered sites was located at AP-1 binding sites. We suggest that AP-1 expression is triggered by hypoxia and interacts with DNA methyltransferases (DNMTs) to target methylation at specific sites in the genome, thus causing suppression of the associated genes that are responsible for differentiation of villous cytotrophoblast to syncytiotrophoblast.
Ryan K C Yuen; Baosheng Chen; John D Blair; Wendy P Robinson; D Michael Nelson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-11
Journal Detail:
Title:  Epigenetics : official journal of the DNA Methylation Society     Volume:  8     ISSN:  1559-2308     ISO Abbreviation:  Epigenetics     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-03-04     Completed Date:  2013-09-06     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  101265293     Medline TA:  Epigenetics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  192-202     Citation Subset:  IM    
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MeSH Terms
Anoxia / genetics*
Antigens, CD59 / genetics,  metabolism
Binding Sites
Cell Differentiation / drug effects,  genetics
Cells, Cultured
CpG Islands
DNA Methylation*
Epigenesis, Genetic*
Gene Expression
Oxygen / metabolism,  pharmacology
Pre-Eclampsia / genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction / methods
Trans-Activators / genetics,  metabolism
Transcription Factor AP-1 / genetics,  metabolism
Trophoblasts / cytology,  drug effects,  physiology*
Grant Support
HD 29190/HD/NICHD NIH HHS; //Canadian Institutes of Health Research
Reg. No./Substance:
0/Antigens, CD59; 0/Trans-Activators; 0/Transcription Factor AP-1; 0/ZNF217 protein, human; 101754-01-2/CD59 protein, human; S88TT14065/Oxygen

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