The Epigenetic Reader BRD2 as a Specific Modulator of PAI-1 Expression in Lipopolysaccharide-Stimulated Mouse Primary Astrocytes

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• 作者：Chang Soon Choi ; Seong Hwi Hong ; Seobo Sim ; Kyu Suk Cho…
• 关键词：BRD2 ; Plasminogen activator inhibitor ; 1 ; Inflammation ; Astrocyte ; JQ1
• 刊名：Neurochemical Research
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：40
• 期：11
• 页码：2211-2219
• 全文大小：1,399 KB
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• 作者单位：Chang Soon Choi (1)
  Seong Hwi Hong (2)
  Seobo Sim (3) (5)
  Kyu Suk Cho (1)
  Ji-Woon Kim (1)
  Sung Min Yang (1)
  Se Jin Jeon (4)
  Jueng Soo You (2) (3) (7)
  Chan Young Shin (1) (3) (6)
  
  1. Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea
  2. Department of Biochemistry, School of Medicine, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea
  3. KU Open Innovation center, Konkuk University, Seoul, 143-701, Korea
  5. Department of Environmental and Tropical Medicine, School of Medicine, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea
  4. Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Korea
  7. Department of Biochemistry, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong Kwangjin-Gu, Seoul, 143-701, Korea
  6. Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong Kwangjin-Gu, Seoul, 143-701, Korea
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Neurosciences
  Biochemistry
  Neurology
  
• 出版者：Springer Netherlands
• ISSN：1573-6903

文摘

The post translational modification of lysine acetylation is a key mechanism that regulates chromatin structure. Epigenetic readers, such as the BET domains, are responsible for reading histone lysine acetylation which is a hallmark of open chromatin structure, further providing a scaffold that can be accessed by RNA polymerases as well as transcription factors. Recently, several reports have assessed and highlighted the roles of epigenetic readers in various cellular contexts. However, little is known about their role in the regulation of inflammatory genes, which is critical in exquisitely tuning inflammatory responses to a variety of immune stimuli. In this study, we investigated the role of epigenetic readers BRD2 and BRD4 in the lipopolysaccharide (LPS)-induced immune responses in mouse primary astrocytes. Inflammatory stimulation by LPS showed that the levels of Brd2 mRNA and protein were increased, while Brd4 mRNA levels did not change. Knocking down of Brd2 mRNA using specific small interfering RNA (siRNA) in cultured mouse primary astrocytes inhibited LPS-induced mRNA expression and secretion of plasminogen activator inhibitor-1 (PAI-1). However, no other pro-inflammatory cytokines, such as Il-6, Il-1β and Tnf-α, were affected. Indeed, treatment with bromodomain-containing protein inhibitor, JQ1, blocked Pai-1 mRNA expression through the inhibition of direct BRD2 protein-binding and active histone modification on Pai-1 promoter. Taken together, our data suggest that BRD2 is involved in the modulation of neuroinflammatory responses through PAI-1 and via the regulation of epigenetic reader BET protein, further providing a potential novel therapeutic strategy in neuroinflammatory diseases.