Here, we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which 
demethylates histone H3 on Lys4 or Lys9 (H3K4/K9), is an indispensible 
epigenetic governor of hematopoietic differentiation. Integrative genomic 
analysis, combining global occupancy of Lsd1, genome-wide analysis of its 
substrates H3K4 monomethylation and dimethylation, and gene expression 
profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell 
(HSPC) gene expression programs during hematopoietic differentiation. We found 
that Lsd1 acts at transcription start sites, as well as enhancer regions. Loss 
of Lsd1 was associated with increased H3K4me1 and H3K4me2 methylation on HSPC 
genes and gene derepression. Failure to fully silence HSPC genes compromised 
differentiation of hematopoietic stem cells as well as mature blood cell 
lineages. Collectively, our data indicate that Lsd1-mediated concurrent 
repression of enhancer and promoter activity of stem and progenitor cell genes 
is a pivotal epigenetic mechanism required for proper hematopoietic maturation. 
DOI:http://dx.doi.org/10.7554/eLife.00633.001.