What is the role of lysine-specific demethylase 1 (LSD1) in hematopoiesis?
LSD1 represents a central regulator of hematopoietic stem and progenitor cells. LSD1 knockdown (LSD1-kd) expanded progenitor numbers by enhancing their proliferative behavior. LSD1-kd led to an extensive expansion of granulomonocytic, erythroid and megakaryocytic progenitors. In contrast, terminal granulopoiesis, erythropoiesis and platelet production were severely inhibited. The only exception was monopoiesis, which was promoted by LSD1 deficiency. Importantly, we showed that peripheral blood granulocytopenia, monocytosis, anemia and thrombocytopenia were reversible after LSD1-kd termination. Extramedullary splenic hematopoiesis contributed to the phenotypic reversion, and progenitor populations remained expanded. LSD1-kd was associated with the upregulation of key hematopoietic genes, including Gfi1b, Hoxa9 and Meis1, which are known regulators of the HSC/progenitor compartment. We also demonstrated that LSD1-kd abrogated Gfi1b-negative autoregulation by crossing LSD1-kd with Gfi1b:GFP mice. There is also epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b that is mediated by the cofactors CoREST and LSD1. A short Gfi-1B isoform controls erythroid differentiation by recruiting the LSD1-CoREST complex through the dimethylation of its SNAG domain. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore,  the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated 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 in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. 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, it appears that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs. Furthermore, RUNX1 has been shown to be part of a large transcription factor complex, together with LDB1, GATA1, TAL1, and ETO2 in erythroid cells. RUNX1 interacts with LSD1 and MYEF2 in erythroid cells. MYEF2 is bound in undifferentiated cells and is lost upon differentiation, whereas LSD1 is bound in differentiated cells. Finally, LSD1 also participates in the trans-repressive effects of SALL4. Based on luciferase assays, the amine oxidase domain of LSD1 is important in suppressing SALL4-mediated reporter transcription. In freshly isolated adult mouse bone marrows, both SALL4 and LSD1 proteins are preferentially expressed in undifferentiated progenitor cells and co-localize in the nuclei. Further sequential chromatin immunoprecipitation assay confirmed that these two factors share the same binding sites at the promoter regions of important hematopoietic regulatory genes including EBF1, GATA1, and TNF.