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

Mickael Mathieu (1) , Coralie Drelon (1) , Stéphanie Rodriguez (1) , Houda Tabbal (2) , Amandine Septier (1) , Christelle Damon-Soubeyrand (1) , Typhanie Dumontet (1) , Annabel Berthon (2) , Isabelle Sahut-Barnola (1) , Cyril Djari (1) , Marie Batisse-Lignier (1) , Jean-Christophe Pointud (1) , Damien Richard Richard (3) , Gwenneg Kerdivel (4) , Marie-Ange Calméjane (4) , Valentina Boeva (4) , Igor Tauveron (1) , Anne-Marie Lefrançois-Martinez (1) , Antoine Martinez (1) , Pierre Val (1)

1 GReD - Génétique, Reproduction et Développement
2 GReD - Génétique, Reproduction et Développement
3 CHU Gabriel Montpied [Clermont-Ferrand]
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin

Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endo-crine 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 phospho-diesterases 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. adrenal | differentiation | progenitors | PKA signaling | EZH2

Domaines: Embryologie et organogenèse; Biochimie, Biologie Moléculaire; Cancer; Génétique animale; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Endocrinologie et métabolisme

Mickael Mathieu, Coralie Drelon, Stéphanie Rodriguez, Houda Tabbal, Amandine Septier, et al.. Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (52), pp.E12265-E12274. ⟨10.1073/pnas.1809185115⟩. ⟨hal-02324493⟩