title: Epigenetic Regulation of Tissue-Type Plasminogen Activator in Human Brain Tissue and Brain-Derived Cells.
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.
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Experimental Cardiovascular Research Unit, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Hultman
authors.affiliation: Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dunoyer-Geindre
authors.affiliation: Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.affiliation: Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Egbert K O
authors.initials: EK
authors.lastname: Kruithof
authors.affiliation: Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Jern
keywords: DNA methylation; brain tissue; histone acetylation; tissue-type plasminogen activator
references.citation: Cardiovasc Res. 2011 Jun 1;90(3):457-63
references.pmid: 21282301
references.citation: Physiol Rev. 2011 Apr;91(2):603-49
references.pmid: 21527733
references.citation: Lab Invest. 2010 Feb;90(2):282-90
references.pmid: 20010852
references.citation: Stroke. 2009 Aug;40(8):2899-905
references.pmid: 19478231
references.citation: Int J Biochem Cell Biol. 2007;39(7-8):1388-405
references.pmid: 17383217
references.citation: Thromb Haemost. 2004 Aug;92(2):358-68
references.pmid: 15269833
references.citation: J Neurosci. 2007 Jun 6;27(23):6128-40
references.pmid: 17553985
references.citation: Neuron. 2006 Jun 1;50(5):673-8
references.pmid: 16731507
references.citation: Trends Neurosci. 2004 Mar;27(3):155-60
references.pmid: 15036881
references.citation: Nature. 1995 Sep 28;377(6547):340-4
references.pmid: 7566088