Ectopic TLX expression skews lineage commitment toward a myeloid fate and promotes an inflammatory phenotype. Mus musculus

We previously showed that the orphan nuclear hormone receptor, TLX (also known as NR2E1), selectively modifies the output of IFN-gamma-driven, STAT1-dependent gene expression. Since IFN-gamma and STAT1 are also known to regulate myeloid cell development and function, we tested whether ectopic expression of TLX or COUPTF2 (a closely related orphan nuclear receptor) might influence hematopoietic differentiation. Indeed, TLX promotes lineage commitment toward myeloid development and suppresses erythropoiesis, phenocopying IFN-gamma treatment. Moreover, TLX expression in our assay is sufficient to activate a proinflammatory transcriptional program with two hallmarks: differential regulation of STAT1-dependent genes, and suppression of an anti-inflammatory program in favor of a fatty acid signature – a process known to be essential for cellular remodeling during macrophage maturation and phagocytosis. These results demonstrate an important role for a new nuclear hormone receptor in STAT1 signaling, and link TLX to myeloid lineage commitment and function. Overall design: Cells purified from three different experiments were analyzed as biological triplicates for four different treatments.