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Significance The adrenal cortex plays a central role in regulating body homeostasis through production of glucocorticoids and mineralocorticoids that control metabolism, inflammation, and blood pressure. The production of these hormones, known as steroidogenesis, is achieved by differentiated steroidogenic cells that arise from undifferentiated progenitors and are constantly renewed throughout life. Until now, the mechanisms that ensured that progenitors differentiated as steroidogenic cells and maintained this differentiated state were unknown. Our data show that the histone methyltransferase EZH2, a key epigenetic factor, is the central regulator of this process. Consequently, adrenal-specific EZH2 knockout mice fail to normally differentiate steroidogenic cells, which results in a life-threatening condition known as primary glucocorticoid insufficiency in patients.

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