The epigenetic eraser LSD1 lies at the apex of a reversible erythroid to myeloid cell fate decision

AbstractHistone H3 lysine 4 methylation (H3K4Me) is proximally associated with chromatin activation, and therefore removing H3K4 methyl groups is normally coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a potential therapeutic target for multiple diseases, including for the treatment of the {beta}-globinopathies (sickle cell disease and {beta}-thalassemia) since it is a component of multiple{gamma} -globin repressor complexes, and its inactivation leads to robust induction of the fetal globin genes. However, the effects of LSD1 inhibition in definitive erythroid cells are not well characterized. Here we examined the consequences of erythroid-specific conditional inactivation of Lsd1 in vivo using a new Gata1creERT2 bacterial artificial chromosome (BAC) transgene. Conditional loss of Lsd1 in adult mice led to a differentiation block in erythroid progenitor cells and the surprising expansion of a GMP-like cell pool, apparently converting hematopoietic differentiation potential from an erythroid to a myeloid fate. The analogous phenotype was also observed in human cells: inactivation of LSD1 in hematopoietic stem and progenitor cells (HSPC) also blocked erythroid differentiation, coincident with robust induction of myeloid transcription factor genes (e.g. Pu.1 and Cebpa). Remarkably, blocking the activity of PU.1 or RUNX1 (a transcriptional activator of Pu.1) at the same time as blocking LSD1 activity reverted the myeloid lineage conversion back to an erythroid phenotype. Taken together, the data show that LSD1 maintains erythropoiesis by reversibly repressing a myeloid cell fate in adult erythroid cell precursors, and that inhibition of the myeloid differentiation pathway can reverse the negative effects of LSD1 inactivation on erythroid differentiation.