Phenotypic switching induced by damaged matrix is associated with DNA methyltransferase 3A (DNMT3A) activity and nuclear localization in smooth muscle cells (SMC)

Autor: Jia-Xin, Jiang, Karen J, Aitken, Chris, Sotiropoulos, Chris, Sotiropolous, Tyler, Kirwan, Trupti, Panchal, Nicole, Zhang, Shuye, Pu, Shoshana, Wodak, Cornelia, Tolg, Darius J, Bägli
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Protein Denaturation
Time Factors
Anatomy and Physiology
Methyltransferase
Transcription
Genetic
Muscle Functions
Intracellular Space
lcsh:Medicine
Cell Count
Matrix (biology)
Biochemistry
DNA Methyltransferase 3A
Extracellular matrix
Molecular cell biology
0302 clinical medicine
Myosin
DNA (Cytosine-5-)-Methyltransferases
lcsh:Science
Musculoskeletal System
0303 health sciences
Pediatric Urology
Multidisciplinary
Extracellular Matrix
Nucleic acids
Protein Transport
Phenotype
CpG site
030220 oncology & carcinogenesis
DNA methylation
Medicine
Muscle
Epigenetics
Collagen
DNA modification
Signal Transduction
Research Article
Cell Physiology
Urology
Myocytes
Smooth Muscle
Active Transport
Cell Nucleus
Biophysics
Mitosis
Biology
Gene Expression Regulation
Enzymologic
Muscle Types
03 medical and health sciences
Genetics
Animals
Humans
Actin
Cell Proliferation
030304 developmental biology
Cell Nucleus
lcsh:R
DNA
Cell Dedifferentiation
DNA Methylation
Molecular biology
Rats
Protein Biosynthesis
lcsh:Q
Gene expression
Zdroj: PLoS ONE, Vol 8, Iss 8, p e69089 (2013)
PLoS ONE
ISSN: 1932-6203
Popis: 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% O2 (balanced 5% CO2 and 95% N2) 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.
Databáze: OpenAIRE
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