Phenotypic Switching Induced by Damaged Matrix Is Associated with DNA Methyltransferase 3A

Extracellular matrix changes are often crucial inciting events for fibroproliferative disease. Epigenetic changes, specifically DNA methylation, are critical factors underlying differentiated phenotypes. We examined the dependency of matrix-induced fibroproliferation and SMC phenotype on DNA methylt...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2013-08, Vol.8 (8), p.e69089
Main Authors: Jiang, Jia-Xin, Aitken, Karen J, Sotiropolous, Chris, Kirwan, Tyler, Panchal, Trupti, Zhang, Nicole, Pu, Shuye, Wodak, Shoshana, Tolg, Cornelia, Bägli, Darius J
Format: Article
Language:English
Subjects:
Analysis
Collagen
DNA
Epigenetic inheritance
Genes
Methylation
Methyltransferases
Muscle proteins
Myosin
Smooth muscle
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Extracellular matrix changes are often crucial inciting events for fibroproliferative disease. Epigenetic changes, specifically DNA methylation, are critical factors underlying differentiated phenotypes. We examined the dependency of matrix-induced fibroproliferation and SMC phenotype on DNA methyltransferases. The cooperativity of matrix with growth factors, cell density and hypoxia was also examined. Primary rat visceral SMC of early passage (0-2) were plated on native collagen or damaged/heat-denatured collagen. Hypoxia was induced with 3% O.sub.2 (balanced 5% CO.sub.2 and 95% N.sub.2) over 48 hours. Inhibitors were applied 2-3 hours after cells were plated on matrix, or immediately before hypoxia. Cells were fixed and stained for DNMT3A and smooth muscle actin (SMA) or smooth muscle myosin heavy chain. Illumina 450 K array of CpG sites was performed on bisulfite-converted DNA from smooth muscle cells on damaged matrix vs native collagen. Matrix exquisitely regulates DNMT3A localization and expression, and influences differentiation in SMCs exposed to denatured matrix +/- hypoxia. Analysis of DNA methylation signatures showed that Matrix caused significant DNA methylation alterations in a discrete number of CpG sites proximal to genes related to SMC differentiation. Matrix has a profound effect on the regulation of SMC phenotype, which is associated with altered expression, localization of DNMTs and discrete changes DNA methylation.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0069089