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

Olsson, Martina; Hultman, Karin LU ; Dunoyer-Geindre, Sylvie; Curtis, Maurice A; Faull, Richard L M; Kruithof, Egbert K O and Jern, Christina (2016) In Gene Regulation and Systems Biology 10. p.9-13
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... (More)
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. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Gene Regulation and Systems Biology
volume
10
pages
9 - 13
publisher
Libertas Academica Ltd.
external identifiers
  • pmid:26823649
  • scopus:84962052409
  • wos:000387841300002
ISSN
1177-6250
DOI
10.4137/GRSB.S30241
language
English
LU publication?
yes
id
659662ce-f47f-4fe3-8a3b-8d1b73ff3e7c (old id 8572988)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26823649?dopt=Abstract
date added to LUP
2016-02-05 21:08:37
date last changed
2017-09-18 11:29:20
@article{659662ce-f47f-4fe3-8a3b-8d1b73ff3e7c,
  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.},
  author       = {Olsson, Martina and Hultman, Karin and Dunoyer-Geindre, Sylvie and Curtis, Maurice A and Faull, Richard L M and Kruithof, Egbert K O and Jern, Christina},
  issn         = {1177-6250},
  language     = {eng},
  pages        = {9--13},
  publisher    = {Libertas Academica Ltd.},
  series       = {Gene Regulation and Systems Biology},
  title        = {Epigenetic Regulation of Tissue-Type Plasminogen Activator in Human Brain Tissue and Brain-Derived Cells.},
  url          = {http://dx.doi.org/10.4137/GRSB.S30241},
  volume       = {10},
  year         = {2016},
}