Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation

Significance We have long known that thyroid hormone (TH) stimulates formation of red blood cells and patients with thyroid diseases are often anemic, but the underlying molecular mechanisms are unclear. This study uses pharmacologic and genetic approaches in primary cells and animal models to demonstrate essential roles of nuclear receptor coactivator 4 (NCOA4) and TH in late erythropoiesis. We show that TH is essential for the last steps in formation of red cells in culture, and that treatment of cells with drugs that activate a particular nuclear TH receptor, TRβ, stimulates erythroid differentiation and alleviates anemic symptoms in a chronic anemia mouse model, indicating potential clinical applications. Further, we show that TRβ functions together with NCOA4 to regulate red cell formation.