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

Tamer Sallam, Marius Jones, Brandon J. Thomas, Xiaohui Wu, Thomas Gilliland, Kevin Qian, Ascia Eskin, David Casero, Zhengyi Zhang, Jaspreet Sandhu, David Salisbury, Prashant Rajbhandari, Mete Civelek, Cynthia Hong, Ayaka Ito, Xin Liu, Bence Daniel, Aldons J. Lusis, Julian Whitelegge, Laszlo NagyAntonio Castrillo, Stephen Smale, Peter Tontonoz

Research output: Article

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)304-312
Number of pages9
JournalNature medicine
Volume24
Issue number3
DOIs
Publication statusPublished - márc. 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sallam, T., Jones, M., Thomas, B. J., Wu, X., Gilliland, T., Qian, K., Eskin, A., Casero, D., Zhang, Z., Sandhu, J., Salisbury, D., Rajbhandari, P., Civelek, M., Hong, C., Ito, A., Liu, X., Daniel, B., Lusis, A. J., Whitelegge, J., ... Tontonoz, P. (2018). Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nature medicine, 24(3), 304-312. https://doi.org/10.1038/nm.4479