GSE40440
Histone Demethylase Lsd1 is Required to Repress Hematopoietic Stem and Progenitor Cell Signatures During Blood Cell Maturation
Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on Lys?4 or Lys?9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages.  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. Overall design: To identify direct target genes of Lsd1 in myeloid cells we mapped global occupancy of Lsd1 in 32D granuolocytic progenitor cells and compared H3K4me1/me2/me3 and H3K27ac histone modifications in Lsd1fl/fl (wild type) vs. Lsd1fl/f Mx1Cre (knockout) Gr1dim Mac1 granuolocytic progenitor cells.