Journal Article

Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

Mathieu, Mickael, Lefrançois-Martinez, Anne-Marie, Tabbal, Houda, Septier, Amandine, Boeva, Valentina, Rodriguez, Stéphanie, Drelon, Coralie, Tauveron, Igor, Calméjane, Marie-Ange, Dumontet, Typhanie, Sahut-Barnola, Isabelle, Richard, Damien, Val, Pierre, Berthon, Annabel, Pointud, Jean-Christophe, Kerdivel, Gwenneg, Djari, Cyril, Martinez, Antoine, Damon-Soubeyrand, Christelle, Batisse-Lignier, Marie

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Ablation / Adrenal cortex / Adrenal Cortex - enzymology / Adrenal Cortex - metabolism / Adrenal glands / Adrenocorticotropic hormone / Animal genetics / Animals / Biochemistry, Molecular Biology / Biological Sciences / Ca2+/calmodulin-dependent phosphodiesterase / Cancer / Cell Differentiation / Cells (biology) / Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - genetics / Cyclic AMP-Dependent Protein Kinase RIbeta Subunit - metabolism / Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics / Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism / Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics / Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism / Cyclic Nucleotide Phosphodiesterases, Type 7 - genetics / Cyclic Nucleotide Phosphodiesterases, Type 7 - metabolism / Development Biology / Developmental Biology / Differential equations / Differentiation (biology) / Embryology and Organogenesis / Endocrinology and metabolism / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / Female / Genetics / Genomics / Glucocorticoids / Histone methyltransferase / Homeostasis / Human health and pathology / Life Sciences / Male / Mice, Inbred C57BL / Mice, Knockout / PNAS Plus / Progenitor cells / Protein kinase A / Signal Transduction / Signaling / Stem cells / Steroid hormones / Steroids / Steroids - metabolism / Zona Fasciculata - cytology / Zona Fasciculata - enzymology / Zona Fasciculata - metabolism / Zona Glomerulosa - cytology / Zona Glomerulosa - enzymology / Zona Glomerulosa - metabolism