Aims

In hepatocytes, the retinoic acid receptor-related orphan receptor α (RORα) regulates the transcription of diverse genes encoding lipogenic enzymes, antioxidant enzymes, and mitochondrial factors via the regulation of the transcriptional activity of their promoters. The coordination of the expression of RORα by driving its transcription would provide better aspects for managing liver homeostasis.

Main methods

The transcriptional expression of RORα was measured after treatment of RORα agonists on primary hepatocytes and liver. The histone status of Rora gene bodies was examined by analyzing ChIP-seq database. To elucidate molecular mechanism for RORα autoregulation, broad ChIP assays for promoters and enhancers with histone and RORα antibodies were performed.

Key findings

We report that natural and synthetic RORα agonists, cholesterol sulfate and JC1–40, respectively, increased the transcriptional expression of RORα in primary hepatocytes. An analysis of histone status around the Rora gene body identified promoter and enhancer regions of RORα. We found that RORα indirectly increased histone acetylation of H3K9 at the promoter region and directly enhanced histone monomethylation of H3K4 by binding to enhancer regions. Interestingly, disturbance of mixed-lineage leukemia 4 (MLL4), a histone methyltransferase for enhancers, abolished the JC1–40-induced activation of RORα via a decrease in H3K4me1. Finally, we observed that the MLL4-mediated autoregulation of RORα also occurred in human liver cancer cell lines.

Significance

The ability of RORα to modulate its own transcription is crucial for liver homeostasis, and ligand-dependent autoregulation could amplify the therapeutic effects of RORα in fatty liver diseases.

中文翻译：

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RORα通过与肝脏中MLL4相关的增强子重塑自动调节其转录。

目的

在肝细胞中，视黄酸受体相关的孤儿受体α（RORα）通过调节启动子的转录活性来调节编码脂肪生成酶，抗氧化酶和线粒体因子的各种基因的转录。通过驱动RORα的转录来协调RORα的表达，将为管理肝稳态提供更好的方面。

主要方法

在原代肝细胞和肝脏上处理RORα激动剂后，测量RORα的转录表达。通过分析ChIP-seq数据库检查了Rora基因体的组蛋白状态。为了阐明RORα自动调节的分子机制，对具有组蛋白和RORα抗体的启动子和增强子进行了广泛的ChIP分析。

主要发现

我们报道天然和合成的RORα激动剂，硫酸胆固醇和JC1–40分别增加了原代肝细胞中RORα的转录表达。周围的组蛋白状态的分析RORA基因体鉴定启动子和RORα的增强区域。我们发现RORα间接增加了启动子区域H3K9的组蛋白乙酰化，并通过结合增强子区域直接增强了H3K4的组蛋白单甲基化。有趣的是，混合谱系白血病4（MLL4）（一种用于增强子的组蛋白甲基转移酶）的干扰通过降低H3K4me1消除了JC1-40诱导的RORα激活。最后，我们观察到在人类肝癌细胞系中也发生了MLL4介导的RORα的自动调节。

意义

RORα调节其自身转录的能力对于肝脏体内稳态至关重要，而依赖配体的自动调节可增强RORα在脂肪肝疾病中的治疗作用。