Glucocorticoid-induced Fingerprints on Visceral Adipose Tissue Transcriptome and Epigenome

Guillermo García-Eguren, Mar González-Ramírez, Pedro Vizán, Oriol Giró, Arturo Vega-Beyhart, Laura Boswell, Mireia Mora, Irene Halperin, Francisco Carmona, Meritxell Gracia, Gregori Casals, Mattia Squarcia, Joaquim Enseñat, Oscar Vidal, Luciano Di Croce, Felicia A. Hanzu

Research output: Indexed journal article Articlepeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)150-166
Number of pages17
JournalJournal of Clinical Endocrinology and Metabolism
Volume107
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022
Externally publishedYes

Keywords

  • Cushing's syndrome
  • circadian rhythm
  • epigenome
  • glucocorticoids
  • transcriptome
  • visceral adipose tissue

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