Effect of Regulatory Element DNA Methylation on Tissue-Type Plasminogen Activator Gene Expression.

Published on Jan 1, 2016in PLOS ONE2.74
· DOI :10.1371/JOURNAL.PONE.0167588
Sylvie Dunoyer-Geindre16
Estimated H-index: 16
(University of Geneva),
Anne-Sophie Rivier-Cordey4
Estimated H-index: 4
(University of Geneva)
+ 2 AuthorsEgbert K. O. Kruithof41
Estimated H-index: 41
(University of Geneva)
: Expression of the tissue-type plasminogen activator gene (t-PA; gene name PLAT) is regulated, in part, by epigenetic mechanisms. We investigated the relationship between PLAT methylation and PLAT expression in five primary human cell types and six transformed cell lines. CpG methylation was analyzed in the proximal PLAT gene promoter and near the multihormone responsive enhancer (MHRE) -7.3 kilobase pairs upstream of the PLAT transcriptional start site (TSS, -7.3 kb). In Bowes melanoma cells, the PLAT promoter and the MHRE were fully unmethylated and t-PA secretion was extremely high. In other cell types the region from -647 to -366 was fully methylated, whereas an unmethylated stretch of DNA from -121 to +94 was required but not sufficient for detectable t-PA mRNA and t-PA secretion. DNA methylation near the MHRE was not correlated with t-PA secretion. Specific methylation of the PLAT promoter region -151 to +151, inserted into a firefly luciferase reporter gene, abolished reporter gene activity. The region -121 to + 94 contains two well-described regulatory elements, a PMA-responsive element (CRE) near -106 and a GC-rich region containing an Sp1 binding site near +59. Methylation of double-stranded DNA oligonucleotides containing the CRE or the GC-rich region had little or no effect on transcription factor binding. Methylated CpGs may attract co-repressor complexes that contain histone deacetylases (HDAC). However, reporter gene activity of methylated plasmids was not restored by the HDAC inhibitor trichostatin. In conclusion, efficient PLAT gene expression requires a short stretch of unmethylated CpG sites in the proximal promoter.
📖 Papers frequently viewed together
41 Citations
152 Citations
5 Citations
#1Soo Heon Kwak (Seoul National University Hospital)H-Index: 30
#2Kyong Soo Park (SNU: Seoul National University)H-Index: 81
Type 2 diabetes (T2DM) is a common complex metabolic disorder that has a strong genetic predisposition. During the past decade, progress in genetic association studies has enabled the identification of at least 75 independent genetic loci for T2DM, thus allowing a better understanding of the genetic architecture of T2DM. International collaborations and large-scale meta-analyses of genome-wide association studies have made these achievements possible. However, whether the identified common varia...
84 CitationsSource
#1Martina Barnevik Olsson (University of Gothenburg)H-Index: 8
#2Karin Hultman (Lund University)H-Index: 11
Last. Christina Jern (University of Gothenburg)H-Index: 43
view all 7 authors...
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 neur...
2 CitationsSource
Changes in eating habits and sedentary lifestyle are main contributors to type 2 diabetes (T2D) development, and studies suggest that epigenetic modifications are involved with the growing incidence of this disease. Regular exercise modulates many intracellular pathways improving insulin resistance and glucose uptake in skeletal muscle, both early abnormalities of T2D. Mitochondria dysfunction and decreased expression of glucose transporter (GLUT4) were identified as main factors of insulin resi...
41 CitationsSource
#1Mia Magnusson (University of Gothenburg)H-Index: 4
#2Emma Lu (University of Gothenburg)H-Index: 5
Last. Sverker Jern (University of Gothenburg)H-Index: 51
view all 7 authors...
Tissue-type plasminogen activator (t-PA), which is synthesized in the endothelial cells lining the blood vessel walls, is a key player in the fibrinolytic system protecting the circulation against occluding thrombus formation. Although classical gene regulation has been quite extensively studied in order to understand the mechanisms behind t-PA regulation, epigenetics, including DNA methylation, still is a largely unexplored field. The aim of this study was to establish the methylation pattern i...
6 CitationsSource
#1Tina Rönn (Lund University)H-Index: 29
#2Charlotte Ling (Lund University)H-Index: 63
Type 2 diabetes (T2D) develops due to insulin resistance and impaired insulin secretion, predominantly in genetically predisposed subjects exposed to nongenetic risk factors like obesity, physical inactivity and ageing. Emerging data suggest that epigenetics also play a key role in the pathogenesis of T2D. Genome-wide studies have identified altered DNA methylation patterns in pancreatic islets, skeletal muscle and adipose tissue from subjects with T2D compared with nondiabetic controls. Environ...
61 CitationsSource
#1Xiangru Xu (MPG: Max Planck Society)H-Index: 16
With ever-increasing elder population, the high incidence of age-related diseases such as neurodegenerative disorders has turned out to be a huge public concern. Especially the elders and their families dreadfully suffer from the learning, behavioral and cognitive impairments. The lack of effective therapies for such a horrible symptom makes a great demanding for biological mechanism study for cognitive aging. Epigenetics is an emerging field that broadens the dimensions of mammalian genome blue...
38 CitationsSource
The molecular signatures of epigenetic regulation and chromatin architectures are fundamental to genetically determined biological processes. Covalent and post-translational chemical modification of the chromatin template can sensitize the genome to changing environmental conditions to establish diverse functional states. Recent interest and research focus surrounds the direct connections between metabolism and chromatin dynamics, which now represents an important conceptual challenge to explain...
171 CitationsSource
#1Kristina Svennerholm (University of Gothenburg)H-Index: 5
#2Niklas Bergh (University of Gothenburg)H-Index: 10
Last. Michael Haney (Umeå University)H-Index: 17
view all 7 authors...
BACKGROUND: The expression of the tissue plasminogen activator gene can be affected by histone deacetylation inhibition and thus appears to be under epigenetic control.OBJECTIVES: The study aimed t ...
9 CitationsSource
#1Egbert K. O. Kruithof (University of Geneva)H-Index: 41
#2Sylvie Dunoyer-Geindre (University of Geneva)H-Index: 16
Tissue-type plasminogen activator (t-PA ) plays an important role in the removal of intravascular fibrin deposits and has several physiological roles and pathological activities in the brain. Its production by many other cell types suggests that t-PA has additional functions outside the vascular and central nervous system. Activity of t-PA is regulated at the level of its gene transcription, its mRNA stability and translation, its storage and regulated release, its interaction with cofactors tha...
36 CitationsSource
#1Haoyang Lu (BIT: Beijing Institute of Technology)H-Index: 2
#2Xinzhou Liu (BIT: Beijing Institute of Technology)H-Index: 1
Last. Hong Qing (BIT: Beijing Institute of Technology)H-Index: 26
view all 4 authors...
Epigenetic alterations represent a sort of functional modifications related to the genome that are not responsible for changes in the nucleotide sequence. DNA methylation is one of such epigenetic modifications that are intensively studied during several decades. The transfer of a methyl group to the 5 position of a cytosine is the key feature of DNA methylation. Such a change, though simple, can be caused by various kinds of factors, and also can affect a large number of severe diseases, includ...
116 CitationsSource
Cited By6
#1Elisa Danese (University of Verona)H-Index: 31
#2Martina Montagnana (University of Verona)H-Index: 66
Last. Giuseppe Lippi (University of Verona)H-Index: 109
view all 4 authors...
Epigenetics, a term conventionally used to explain the intricate interplay between genes and the environment, is now regarded as the fundament of developmental biology. Several lines of evidence garnered over the past decades suggest that epigenetic alterations, mostly encompassing DNA methylation, histone tail modifications, and generation of microRNAs, play an important, though still incompletely explored, role in both primary and secondary hemostasis. Epigenetic variations may interplay with ...
#1Nicole Moschny (MHH: Hannover Medical School)H-Index: 3
#2Kirsten Jahn (MHH: Hannover Medical School)H-Index: 4
Last. Alexandra Neyazi (MHH: Hannover Medical School)H-Index: 8
view all 10 authors...
Background Major Depressive Disorder (MDD) represents a tremendous health threat to the world’s population. Electroconvulsive therapy (ECT) is the most effective treatment option for refractory MDD patients. Ample evidence suggests brain-derived neurotrophic factor (BDNF) to play a crucial role in ECT´s mode of action. Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) are involved in BDNF production. Hypothesis The DNA methylation of gene regions encoding for...
#1Yulan Liao (Kyung Hee University)H-Index: 3
#2Ho Jung Bae (Kyung Hee University)H-Index: 3
Last. Jong Hoon Ryu (Kyung Hee University)H-Index: 51
view all 10 authors...
: Bee pollen consists of floral pollen mixed with bee secretions and nectar. It has been considered as a functional food and has different kinds of biologically active ingredients, such as flavonoids, polyphenols, phytosterols and minerals. However, its function in cognition has yet been investigated. In the present study, we investigated the ameliorating effect of bee pollen against scopolamine-caused cognitive impairment through the passive avoidance test, the Y-maze test and the Morris water ...
4 CitationsSource
#1Masanori Kidoguchi (University of Fukui)H-Index: 4
#2Emiko Noguchi (University of Tsukuba)H-Index: 35
Last. Shigeharu Fujieda (University of Fukui)H-Index: 40
view all 12 authors...
: Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in ...
5 CitationsSource
#1Awen MenouH-Index: 3
#2JanWillem Duitman (French Institute of Health and Medical Research)H-Index: 4
Last. Bruno Crestani (French Institute of Health and Medical Research)H-Index: 13
view all 3 authors...
Abstract Idiopathic Pulmonary Fibrosis (IPF) is a devastating chronic, progressive and irreversible disease that remains refractory to current therapies. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the development of pulmonary fibrosis since decades. Coagulation signalling deregulation, which influences several key inflammatory and fibro-proliferative responses, is also essential in IPF pathogenesis, and a growing body of evid...
30 CitationsSource
#2Michael P. SarrasH-Index: 11
Last. Michael P. SarrasH-Index: 43
view all 2 authors...