Prox1 Directly Interacts with LSD1 and Recruits the LSD1/NuRD Complex to Epigenetically Co-Repress CYP7A1 Transcription

	Prox1 Directly Interacts with LSD1 and Recruits the LSD1/NuRD Complex to Epigenetically Co-Repress CYP7A1 Transcription
	Ouyang, HF; Qin, Y; Liu, YF; Xie, YH; Liu, J
刊名	PLOS ONE
	2013
卷号	8 期号:4 页码:e62192-e62192
通讯作者	Xie, YH (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China.,yhxie@fudan.edu.cn ; liujing212@fudan.edu.cn
英文摘要	Cholesterol 7 alpha-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classical pathway of bile acids synthesis in liver and is crucial for maintaining lipid homeostasis. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) and alpha(1)-fetoprotein transcription factor (FTF) are two major transcription factors driving CYP7A1 promoter activity in hepatocytes. Previous researches have shown that Prospero-related homeobox (Prox1) directly interacts with both HNF4 alpha and FTF and potently co-represses CYP7A1 transcription and bile acid synthesis through unidentified mechanisms. In this work, mechanisms involved in Prox1-mediated co-repression were explored by identifying Prox1-associated proteins using immunoprecipitation followed by mass spectrometry (IP-MS) methodology. Multiple components of the epigenetically repressive lysine-specific demethylase 1 (LSD1)/nucleosome remodeling and histone deacetylase (NuRD) complex, most notably LSD1 and histone deacetylase 2 (HDAC2), were found to be associated with Prox1 and GST pulldown assay demonstrated that Prox1 directly interacts with LSD1. Sequential chromatin immunoprecipitation (ChIP) assays showed that Prox1 co-localizes with HNF4 alpha, LSD1 and HDAC2 on CYP7A1 promoter in HepG2 cells. Furthermore, by using ChIP assay on HepG2 cells with endogenous Prox1 knocked down by RNA interference, Prox1 was shown to recruit LSD1 and HDAC2 onto CYP7A1 promoter and cause increased H3K4 demethylation. Finally, bile acids treatment of HepG2 cells, which significantly repressed CYP7A1 transcription, resulted in increased Prox1 and LSD1/NuRD complex occupancy on CYP7A1 promoter with a concurrent increase in H3K4 demethylation and H3/H4 deacetylation. These results showed that Prox1 interacts with LSD1 to recruit the repressive LSD1/NuRD complex to CYP7A1 promoter and co-represses transcription through epigenetic mechanisms. In addition, such Prox1-mediated epigenetic repression is involved in the physiologically essential negative feedback inhibition of CYP7A1 transcription by bile acids.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	CHOLESTEROL 7-ALPHA-HYDROXYLASE GENE ; BILE-ACID BIOSYNTHESIS ; HOMEOBOX PROTEIN PROX1 ; HETERODIMER PARTNER ; NUCLEAR RECEPTORS ; LIVER ; CHOLESTEROL-7-ALPHA-HYDROXYLASE ; COREPRESSOR ; ACTIVATOR ; INSIGHTS
收录类别	SCI
语种	英语
WOS记录号	WOS:000318008400152
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/366]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Ouyang, HF,Qin, Y,Liu, YF,et al. Prox1 Directly Interacts with LSD1 and Recruits the LSD1/NuRD Complex to Epigenetically Co-Repress CYP7A1 Transcription[J]. PLOS ONE,2013,8(4):e62192-e62192.
APA	Ouyang, HF,Qin, Y,Liu, YF,Xie, YH,&Liu, J.(2013).Prox1 Directly Interacts with LSD1 and Recruits the LSD1/NuRD Complex to Epigenetically Co-Repress CYP7A1 Transcription.PLOS ONE,8(4),e62192-e62192.
MLA	Ouyang, HF,et al."Prox1 Directly Interacts with LSD1 and Recruits the LSD1/NuRD Complex to Epigenetically Co-Repress CYP7A1 Transcription".PLOS ONE 8.4(2013):e62192-e62192.