The stem cell protein SALL4 plays a critical role in hematopoiesis by regulating 
the cell fate. In primitive hematopoietic precursors, it activates or represses 
important genes via recruitment of various epigenetic factors such as DNA 
methyltransferases, and histone deacylases. Here, we demonstrate that LSD1, a 
histone lysine demethylase, 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. In addition, studies from both 
gain- and loss-of-function models revealed that SALL4 dynamically controls the 
binding levels of LSD1, which is accompanied by a reversely changed histone 3 
dimethylated lysine 4 at the same promoter regions. Finally, shRNA-mediated 
knockdown of LSD1 in hematopoietic precursor cells resulted in altered SALL4 
downstream gene expression and increased cellular activity. Thus, our data 
revealed that histone demethylase LSD1 may negatively regulate SALL4-mediated 
transcription, and the dynamic regulation of SALL4-associated epigenetic factors 
cooperatively modulates early hematopoietic precursor proliferation.