The Epigenetic Reader BRD2 as a Specific Modulator of PAI-1 Expression in Lipopolysaccharide-Stimulated Mouse Primary Astrocytes.
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.
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea.
Chang Soon
CS
Choi
Department of Biochemistry, School of Medicine, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea.
Seong Hwi
SH
Hong
KU Open Innovation center, Konkuk University, Seoul, 143-701, Korea.|Department of Environmental and Tropical Medicine, School of Medicine, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea.
Seobo
S
Sim
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea.
Kyu Suk
KS
Cho
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea.
Ji-Woon
JW
Kim
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea.
Sung Min
SM
Yang
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 130-701, Korea.
Se Jin
SJ
Jeon
Department of Biochemistry, School of Medicine, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea. jsyou@kku.ac.kr.|KU Open Innovation center, Konkuk University, Seoul, 143-701, Korea. jsyou@kku.ac.kr.|Department of Biochemistry, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong Kwangjin-Gu, Seoul, 143-701, Korea. jsyou@kku.ac.kr.
Jueng Soo
JS
You
Department of Neuroscience, School of Medicine and Neuroscience Research Center, Institute SMART-IABS, Konkuk University, Seoul, 143-701, Korea. chanyshin@kku.ac.kr.|KU Open Innovation center, Konkuk University, Seoul, 143-701, Korea. chanyshin@kku.ac.kr.|Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong Kwangjin-Gu, Seoul, 143-701, Korea. chanyshin@kku.ac.kr.
Chan Young
CY
Shin
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering; D058258:Serpin E2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D006657:Histones; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058258:Serpin E2; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C511869:Serpine2 protein, mouse
Astrocyte; BRD2; Inflammation; JQ1; Plasminogen activator inhibitor-1