Abstract

Context

Chronic glucocorticoid (GC) overexposure, resulting from endogenous Cushing’s syndrome (CS) or exogenous GC therapy, causes several adverse outcomes, including persistent central fat accumulation associated with a low-grade inflammation. However, no previous multiomics studies in visceral adipose tissue (VAT) from patients exposed to high levels of unsuppressed GC during active CS or after remission are available yet.

Objective

To determine the persistent VAT transcriptomic alterations and epigenetic fingerprints induced by chronic hypercortisolism.

Methods

We employed a translational approach combining high-throughput data on endogenous CS patients and a reversible CS mouse model. We performed RNA sequencing and chromatin immunoprecipitation sequencing on histone modifications (H3K4me3, H3K27ac, and H3K27me3) to identify persistent transcriptional and epigenetic signatures in VAT produced during active CS and maintained after remission.

Results

VAT dysfunction was associated with low-grade proinflammatory status, macrophage infiltration, and extracellular matrix remodeling. Most notably, chronic hypercortisolism caused a persistent circadian rhythm disruption in VAT through core clock genes modulation. Importantly, changes in the levels of 2 histone modifications associated to gene transcriptional activation (H3K4me3 and H3K27ac) correlated with the observed differences in gene expression during active CS and after CS remission.

Conclusion

We identified for the first time the persistent transcriptional and epigenetic signatures induced by hypercortisolism in VAT, providing a novel integrated view of molecular components driving the long-term VAT impairment associated with CS.

中文翻译：

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糖皮质激素诱导的内脏脂肪组织转录组和表观基因组指纹

摘要

语境

由内源性库欣综合征 (CS) 或外源性 GC 治疗引起的慢性糖皮质激素 (GC) 过度暴露会导致多种不良后果，包括与低度炎症相关的持续中央脂肪堆积。然而，之前还没有关于在活动性 CS 期间或缓解后暴露于高水平未抑制 GC 的患者的内脏脂肪组织 (VAT) 的多组学研究。

客观的

确定由慢性皮质醇增多症引起的持续 VAT 转录组改变和表观遗传指纹。

方法

我们采用了一种转化方法，结合了内源性 CS 患者的高通量数据和可逆的 CS 小鼠模型。我们对组蛋白修饰（H3K4me3、H3K27ac 和 H3K27me3）进行了 RNA 测序和染色质免疫沉淀测序，以确定在活动性 CS 期间产生并在缓解后维持的 VAT 中持续的转录和表观遗传特征。

结果

VAT 功能障碍与低度促炎状态、巨噬细胞浸润和细胞外基质重塑有关。最值得注意的是，慢性皮质醇过多症通过核心时钟基因调节导致 VAT 的持续昼夜节律紊乱。重要的是，与基因转录激活（H3K4me3 和 H3K27ac）相关的 2 种组蛋白修饰水平的变化与在活动性 CS 期间和 CS 缓解后观察到的基因表达差异相关。

结论

我们首次确定了由 VAT 中皮质醇增多症引起的持续转录和表观遗传特征，为驱动与 CS 相关的长期 VAT 损伤的分子成分提供了一种新的综合观点。