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.

中文翻译：

---

长链非编码 RNA 对巨噬细胞胆固醇流出和动脉粥样硬化形成的转录调控。

核受体响应环境线索调节基因表达，但控制核受体细胞类型特异性的分子事件仍然知之甚少。在这里，我们概述了长链非编码 RNA (lncRNA) 在调节肝脏 X 受体 (LXRs) 的细胞类型特异性作用中的作用，LXRs 是调节胆固醇稳态相关基因表达的甾醇激活核受体，并且已被因果联系动脉粥样硬化的发病机制。我们将 lncRNA MeXis 鉴定为基因 Abca1 的 LXR 依赖性转录的放大器，这对于调节胆固醇流出至关重要。缺乏 MeXis 基因的小鼠以组织选择性方式显示 Abca1 表达降低。此外，小鼠骨髓细胞中 MeXis 的缺失会改变 Abca1 基因座的染色体结构，损害细胞对胆固醇超载的反应，并加速动脉粥样硬化的发展。机制研究表明，MeXis 与转录共激活因子 DDX17 相互作用并引导启动子结合。将 MeXis 鉴定为 LXR 依赖性基因表达的 lncRNA 调节剂扩大了对核受体在生理和疾病中的细胞类型选择作用机制的理解。