ECE2017 Oral Communications Adrenal-Basic & Clinical (5 abstracts)
EZH2: a master regulator of adrenal cortex homeostasis and zonation
Mickael Mathieu 1 , Coralie Drelon 2 , Houda Tabbal 1 , Stéphanie Rodriguez 1 , Amandine Septier 1 , Annabel Berthon 3 , David Sainte-Catherine 1 , David Breault 4 & Antoine Martinez 1
1Laboratoire GReD, Clermont-Ferrand, France; 2Albert Einstein College of Medicine, Bronx, New York, USA; 3National Institutes of Health, Bethesda, Maryland, USA; 4Harvard Stem Cell Institute, Boston, Massachusetts, USA.
In adult mice the adrenal cortex is divided, in two distinct functional zones, outermost zona glomerulosa (ZG) and innermost zona fasciculata (ZF), encapsulated by a thin layer of mesenchymal cells (capsule). The adrenal cortex undergoes constant centripetal cell renewal, reliying on recruitment of progenitors located within an outer cortex niche. Progenitors initially differentiate as ZG cells and undergo lineage conversion to ZF as they move within the cortex. This relies on a subtle balance and trans-inhibition between WNT and PKA signalling pathways. Epigenetic histone modifiers are prototypical factors that play essential roles from embryonic development to carcinogenesis. We have recently shown that the histone methyl-transferase EZH2 is overexpressed in adrenal cortex carcinomas where is it associated with poor prognosis and tumour aggressiveness. In order to understand EZH2 function in adrenal physiology, we have developed a mouse model of EZH2 inactivation relying on a floxed allele of EZH2 and the Sf1:Cre driver (EZH2KO). Our analyses show adrenal hypoplasia and primary corticosterone insufficiency, associated with expansion of ZG at the expense of ZF and aberrant mixed ZG/ZF differentiation. Consistent with the role of PKA and WNT signalling in establishment and maintenance of zonation, WNT pathway is increased whereas PKA activity is decreased in EZH2KO adrenals. In addition to zonation defects, EZH2KO present abnormal accumulation of ‘stress progenitors’. Recruitment of these particular progenitors is under control of WT1 and GATA4. Our in vivo ChIP and expression data show that these two transcription factors are direct targets of the inhibitory action of EZH2 in the adrenal. Altogether, these data suggest completely unanticipated functions of EZH2 in the control of stress progenitors homeostasis through WT1 and GATA4 and adrenal cortex zonation, which rely on a novel interaction between EZH2 and PKA signalling pathway.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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