Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis

Abstract

TR2 and TR4 (NR2C1 and NR2C2, respectively) are evolutionarily conserved nuclear orphan receptors capable of binding direct repeat sequences in a stage-specific manner. Like other nuclear receptors, TR2 and TR4 possess important roles in transcriptional activation or repression with developmental stage and tissue specificity. TR2 and TR4 bind DNA and possess the ability to complex with available cofactors mediating developmental stage-specific actions in primitive and definitive erythrocytes. In erythropoiesis, TR2 and TR4 are required for erythroid development, maturation, and key erythroid transcription factor regulation. TR2 and TR4 recruit and interact with transcriptional corepressors or coactivators to elicit developmental stage-specific gene regulation during hematopoiesis.

PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease

“…Expression of their embryonic εy- and βh1-globin genes was reduced. Moreover, PGC-1α initiated globin gene transcriptional activation by interacting with nuclear receptors testicular receptor 2/4 (TR2/TR4) ( 19 , 20 ). Forced overexpression of PGC-1α in vitro by adenovirus infection in bone marrow cells from SCD mice resulted in significantly increased expression of human fetal γ-globin genes ( HBG1 and HBG2 , together referred to as HBG ) and εy-globin as well as βh1-globin gene, the murine fetal globin analog ( 21 ).…”