LSD1-mediated Epigenetic Modification Is Required For TAL1 Function And Hematopoiesis

TAL1 is a critical transcription factor required for hematopoiesis. However, perturbation of its activity often leads to T-cell leukemia. How its transcriptional activities are regulated during hematopoiesis remains to be addressed. Here, we showed that TAL1 is associated with histone demethylase complexes containing LSD1, CoREST, HDAC1 and HDAC2 in erythroleukemia and T-cell leukemia cells. The H3K4 demethylase activity of LSD1 is required for TAL1 mediated transcriptional repression. Furthermore, we demonstrated that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately downregulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter only in undifferentiated but not in differentiated murine erythroleukemia (MEL) cells. Finally, the shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1 mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs.