Role of UTX in RAR-mediated gene regulation in leukemia

LUCIANA ROCHA VIEGAS; R. VILLA; A. GUTIERREZ; O. IRIONDO; L. DI CROCE

Los Cocos, Cordoba

Simposio; The First South American Spring Symposium in Signal Transduction and Molecular Medicine (SISTAM); 2010

Human UTX, a member of the Jumonji C family of proteins, associates with mixed-lineage leukemia (MLL) 2/3 complexes, and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Here we show that UTX interacts with the retinoic acid receptor (RAR) and is involved in the differentiation of leukemic U937 cells in response to RA. UTX occupies the promoters of key genes linked to differentiation and regulates their transcriptional output by modulating the recruitment of MLL 2/3 and ASC2 complexes. Moreover, overexpression of UTX in promyelocytic NB4 cells results in enhanced cellular differentiation upon RA treatment. Our results suggest a concerted mechanism for transcriptional activation during differentiation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX at RA-responsive genes.