Steroidogenic Differentiation and PKA Signaling Are Programmed by Histone Methyltransferase EZH2 in the Adrenal Cortex

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Dec 14

PMID 30541888

Citations 23

Authors

Mickael Mathieu

Coralie Drelon

Stephanie Rodriguez

Houda Tabbal

Amandine Septier

Christelle Damon-Soubeyrand

Typhanie Dumontet

Annabel Berthon

Isabelle Sahut-Barnola

Cyril Djari

Marie Batisse-Lignier

Jean-Christophe Pointud

Damien Richard

Gwenneg Kerdivel

Marie-Ange Calmejane

Valentina Boeva

Igor Tauveron

Anne-Marie Lefrancois-Martinez

Antoine Martinez

Pierre Val

Affiliations

Soon will be listed here.

Abstract

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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