ECE2020 Audio ePoster Presentations Adrenal and Cardiovascular Endocrinology (121 abstracts)
Persistent transcriptional disruption and histone mark modifications on visceral adipose tissue after remission of hypercortisolism
Guillermo García-Eguren 1 , Mar Gonzalez 2 , Pedro Vizan 2 , Oriol Giro 3 , Arturo Beyhart 1 , Mireia Mora 1 , Irene Halperin 1 , Joaquim Enseñat 4 , Oscar Vidal 4 , Francisco Carmona 4 , Luciano DiCroce 2 & Felicia Hanzu 1,3
1Hospital Clinic/IDIBAPS, Endocrinology, Barcelona, Spain; 2Centro de Regulación Genomica, Barcelona, Spain; 3IDIBAPS/Laboratory of Endocrine Disorders, Barcelona, Spain; 4Hospital Clinic/Surgery, Barcelona, Spain
Introduction: Chronic hypercortisolemia during Cushing Syndrome (CS) determines significant changes in the plasticity and function of metabolic tissues like visceral adipose tissue (VAT). Persistence of alterations in VAT function after CS remission is under debate, as data of clinical studies is not consistent due to confounder factors and limited availability of VAT. Animal model of reversible CS presents long-term alterations on VAT after remission. We investigate VAT alterations at transcriptional and epigenetic level during active and after CS remission employing a translational approach in a reversible CS animal model and CS patients.
Methods: VAT was obtained during abdominal laparoscopic interventions from 6 patients with active ACTH-independent CS due to adrenal cortical adenoma and from 12 controls (CTR) with benign non-inflammatory abdominal pathology matched by sex, age, BMI, metabolic and vascular comorbidities. VAT from C57BL/6 mice with active CS induced by chronic oral GC administration (5 weeks) and mice with cured CS (10 weeks after treatment) was compared to that of CTR mice. RNAseq and ChIPseq were used to analyze gene expression profile and histone mark H3K4me3, H3K27me3 and H3K27ac at both time points in the animal model and human VAT. Differentially expressed genes (DESeq2 algorithm, adj. P <0.1; fold-change ≥ 1.5) and putative histone marks associations present in patients were compared with those altered during active and cured CS in the animal model.
Results: Transcriptional analysis of mice VAT revealed 464 up and 366 significantly down-regulated genes persistently altered in active CS and after remission. Gene ontology analysis of the disrupted genes at both times resulted in several pathways and biological process including lipid metabolism, circadian rhythm and inflammation. Moreover, the H3K4me3 and H3K27ac peak- associated genes were commonly maintained at both time points and correlated well with alterations present on gene expression. RNAseq of human VAT showed 69 up and 76 significantly down-regulated genes in CS patients compared to CTR from which 14 genes were commonly altered in the animal model at both time points. Overall analysis of human H3K4m3, H3K27ac and H3K27me3 peaks revealed different profiles between CTR and CS patients. Correlation analysis of commonly altered genes and histone marks signature between mice and human is under process.
Conclusion: Chronic hypercortisolism induces persistent transcriptional disruption in mice VAT long term after remission, from which some are commonly altered in patients with active CS. Potential stable histone marks signatures associated to these persistent altered genes are under study.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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