Acute promyelocytic leukemia (APL) is characterized by the appearance of blasts,
insensitive to physiological retinoic acid (RA)-dependent differentiation and in the
majority of the cases, expressing PML-RAR fusion protein. PML-RAR works as a
dominant negative counterpart of retinoic acid receptor (RAR) and represses its target
genes by cooperating with many epigenetic regulators. Some of the known epigenetic
enzymes involved in the APL pathogenesis also interact with LSD1 in other systems.
LSD1 is a demethylase involved in transcriptional regulation, mainly acting on
dimethylated lysine 4 of Histone H3 (H3K4me2). We showed that LSD1 inhibition
sensitizes an APL cell line to physiological RA concentration. Here we characterize
for the first time mechanistic insights of LSD1 activity in PML-RAR expressing APL
cells. We determined the genomic distribution of LSD1, in particular LSD1 binds
both promoters and candidate enhancer regions. We found that LSD1 works as
finetuners of genes involved in differentiation and cell growth control as assessed by
gene ontology analysis. Moreover, LSD1 modulates H3K4me2 levels at regions
enriched in binding sites of master regulators of the myeloid/monocytic lineage,
suggesting their regulatory potential. We also described a previously unknown large
fraction of genomic loci bound by LSD1 and PR. Commonly bound regions show a
peculiar H3K4me2 enrichment and a subset of them resulted dynamically regulated
upon differentiation, suggesting a functional interplay between the two proteins in
reshaping the local chromatin environment. Overall, our findings contribute to the
mechanistic understanding of the role of LSD1 in the sensitization of APL cells to
differentiation