Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 52, Pages E12265-E12274Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1809185115
Keywords
adrenal; differentiation; progenitors; PKA signaling; EZH2
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Funding
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Universite Clermont Auvergne, La Ligue Contre le Cancer (Allier and Puy de Dome committees)
- Fondation ARC, Societe Francaise d'Endocrinologie
- Agence Nationale de la Recherche [ANR-14-CE12-0007-01-DevMiCar]
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Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.
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