Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA

被引：186

作者：

Sallam, Tamer ^{[1
,2
]}

Jones, Marius ^{[1
]}

Thomas, Brandon J. ^{[3
,4
]}

Wu, Xiaohui ^{[2
]}

Gilliland, Thomas ^{[1
]}

Qian, Kevin ^{[1
]}

Eskin, Ascia ^{[5
]}

Casero, David ^{[1
]}

Zhang, Zhengyi ^{[2
]}

Sandhu, Jaspreet ^{[1
]}

Salisbury, David ^{[1
,2
]}

Rajbhandari, Prashant ^{[1
]}

Civelek, Mete ^{[6
,7
]}

Hong, Cynthia ^{[1
]}

Ito, Ayaka ^{[1
]}

Liu, Xin ^{[3
,4
]}

Daniel, Bence ^{[8
,9
]}

Lusis, Aldons J. ^{[2
,5
]}

Whitelegge, Julian ^{[10
]}

Nagy, Laszlo ^{[8
,9
]}

Castrillo, Antonio ^{[11
,12
]}

Smale, Stephen ^{[3
,4
]}

Tontonoz, Peter ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Mol Biol Inst, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA

[2] Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA

[3] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA

[4] Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90024 USA

[5] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[6] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[7] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA

[8] Sanford Burnham Prebys Med Discovery Inst Lake No, Orlando, FL USA

[9] Res Ctr Mol Med, Dept Biochem & Mol Biol, Orlando, FL USA

[10] Univ Calif Los Angeles, Semel Inst, UCLA Neuropsychiat Inst NPI, Pasarow Mass Spectrometry Lab, Los Angeles, CA USA

[11] Univ Las Palmas Gran Canaria, Univ Autonoma Madrid, CSIC,Unidad Asociada CSIC, Inst Invest Biomed Alberto Sols,Unidad Biomed, Las Palmas Gran Canaria, Spain

[12] ULPGC, IUIBS, Las Palmas Gran Canaria, Spain

来源：

NATURE MEDICINE | 2018年 / 24卷 / 03期

基金：

美国国家卫生研究院;

关键词：

CASSETTE TRANSPORTER 1; GENE-EXPRESSION; BINDING PROTEINS; TANGIER-DISEASE; MICE LACKING; LXR-ALPHA; ATHEROSCLEROSIS; GENOME; METABOLISM; CHROMATIN;

D O I：

10.1038/nm.4479

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type-selective actions of nuclear receptors in physiology and disease.

引用

页码：304 / +

页数：12

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[1] Coordinate regulation of transcription and splicing by steroid receptor coregulators [J].