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

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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Figure 1: LXR regulates the noncoding RNA MeXis.
Figure 2: MeXis regulates Abca1 expression and function.
Figure 3: Loss of MeXis impairs macrophage Abca1 expression and accelerates atherosclerosis.
Figure 4: MeXis alters chromosome architecture at the Abca1 locus.
Figure 5: Identification of DDX17 as a binding partner of MeXis.
Figure 6: The LXR–MeXis axis in functionally conserved in humans.

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Acknowledgements

We thank members of the Tontonoz, Smale, Black, and Nagy laboratories and the University of California Los Angeles (UCLA) Atherosclerosis Research Unit for technical assistance and useful discussions. This work was supported by the National Institutes of Health grants HL030568, HL066088, HL128822, the Burroughs Wellcome Fund Career Award for Medical Scientists, and the UCLA Cardiovascular Discovery Fund (Lauren B. Leichtman and Arthur E. Levine Investigator Award).

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Authors

Contributions

T.S. and P.T. conceived and designed the study and guided the interpretation of the results and the preparation of the manuscript. P.T. supervised the study, and T.S. managed the daily experiments. X.W. performed most mouse experiments and data analysis, including for the atherosclerosis study. T.S., M.J., T.G., K.Q., Z.Z., J.S., D.S., P.R., C.H., A.I., and X.L. performed various in vivo and in vitro macrophage experiments and data analysis. Bioinformatic data analysis was performed by D.C. and A.E. B.J.T., X.L., and S.S. assisted with ChIP and ATAC-seq experiments, including data analysis. J.W. performed the mass spectrometry analysis. B.D. and L.N. assisted with ChIP and performed experiments defining enhancer landscape at Abca1. A.C. performed ChIP–seq for LXR. M.C. and A.J.L. provided GWAS data and technical guidance for atherosclerosis analysis. T.S. and P.T. edited the manuscript with input from all authors. All authors discussed the results and approved the final version of the manuscript.

Corresponding authors

Correspondence to Tamer Sallam or Peter Tontonoz.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary Figures 1–14 & Supplementary Tables 1,3–4 (PDF 6140 kb)

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Supplementary Table 2

Analysis of lncRNA-adjacent protein-coding genes (XLSX 117 kb)

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Sallam, T., Jones, M., Thomas, B. et al. Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Nat Med 24, 304–312 (2018). https://doi.org/10.1038/nm.4479

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