ROLE OF THE HISTONE DEMETHYLASE LSD1 IN THE REGULATION OF DIFFERENTIATION OF ACUTE PROMYELOCYTIC LEUKEMIA CELLS
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.
Leukemia, LSD1, APL, Settore MED/04 - Patologia Generale
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