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Epigenetic Regulation of Tissue-Type Plasminogen Activator in Human Brain Tissue and Brain-Derived Cells

Journal article
Authors Martina Olsson
Karin Hultman
Sylvie Dunoyer-Geindre
Maurice A Curtis
Richard RL Faull
Egbert KO Kruithof
Christina Jern
Published in Gene Regulation and Systems Biology
Volume 10
Pages 9-13
ISSN 1177-6250
Publication year 2016
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages 9-13
Language en
Links dx.doi.org/10.4137/GRSB.S30241
Keywords tissue-type plasminogen activator, brain tissue, histone acetylation, DNA methylation
Subject categories Molecular medicine (genetics and pathology)

Abstract

The serine protease tissue-type plasminogen activator (t-PA) is involved in both vital physiological brain processes, such as synaptic plasticity, and pathophysiological conditions, such as neurodegeneration and ischemic stroke. Recent data suggest that epigenetic mechanisms play an important role in the regulation of t-PA in human endothelial cells. However, there are limited data on epigenetic regulation of t-PA in human brain-derived cells. We demonstrate that treatment of cultured human neurons and human astrocytes with the histone deacetylase inhibitors trichostatin A (TSA) and MS-275 resulted in a two- to threefold increase in t-PA mRNA and protein expression levels. Next, we performed a chromatin immunoprecipitation assay on treated astrocytes with antibodies directed against acetylated histones H3 and H4 (both markers of gene activation). Treatment with MS-275 and TSA for 24 hours resulted in a significant increase in H3 acetylation, which could explain the observed increase in t-PA gene activity after the inhibition of histone deacety-lation. Furthermore, DNA methylation analysis of cultured human neurons and astrocytes, as well as human postmortem brain tissue, revealed a stretch of unmethylated CpG dinucleotides in the proximal t-PA promoter, whereas more upstream CpGs were highly methylated. Taken together, these results implicate involvement of epigenetic mechanisms in the regulation of t-PA expression in the human brain.

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