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Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA.
Sallam, Tamer; Jones, Marius; Thomas, Brandon J; Wu, Xiaohui; Gilliland, Thomas; Qian, Kevin; Eskin, Ascia; Casero, David; Zhang, Zhengyi; Sandhu, Jaspreet; Salisbury, David; Rajbhandari, Prashant; Civelek, Mete; Hong, Cynthia; Ito, Ayaka; Liu, Xin; Daniel, Bence; Lusis, Aldons J; Whitelegge, Julian; Nagy, Laszlo; Castrillo, Antonio; Smale, Stephen; Tontonoz, Peter.
Afiliação
  • Sallam T; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Jones M; Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, California, USA.
  • Thomas BJ; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Wu X; Department of Microbiology, Immunology, and Molecular Genetics and Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Gilliland T; Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, California, USA.
  • Qian K; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Eskin A; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Casero D; Departement of Human Genetics, University of California Los Angeles, Los Angeles, California, USA.
  • Zhang Z; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Sandhu J; Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, California, USA.
  • Salisbury D; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Rajbhandari P; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Civelek M; Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, California, USA.
  • Hong C; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Ito A; Center for Public Health Genomics and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
  • Liu X; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Daniel B; Department of Pathology and Laboratory Medicine, Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Lusis AJ; Department of Microbiology, Immunology, and Molecular Genetics and Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Whitelegge J; Sanford-Burnham-Prebys Medical Discovery Institute at Lake Nona and Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Orlando, Florida, USA.
  • Nagy L; Department of Medicine, Division of Cardiology, University of California Los Angeles, Los Angeles, California, USA.
  • Castrillo A; Departement of Human Genetics, University of California Los Angeles, Los Angeles, California, USA.
  • Smale S; Pasarow Mass Spectrometry Laboratory, UCLA Neuropsychiatric Institute (NPI)-Semel Institute, University of California Los Angeles, Los Angeles, California, USA.
  • Tontonoz P; Sanford-Burnham-Prebys Medical Discovery Institute at Lake Nona and Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Orlando, Florida, USA.
Nat Med ; 24(3): 304-312, 2018 03.
Article em En | MEDLINE | ID: mdl-29431742
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article