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| Status |
Public on Dec 01, 2021 |
| Title |
LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
The histone de-methylase LSD1 is over-expressed in different haematological tumours, like AML, where it sustains carcinogenesis by promoting the clonogenic potential of leukemic stem cells. Emerging as a promising epigenetic target for the treatment of these tumour types, various LSD1 inhibitors have been developed in the last years, despite their mechanism of action in cancer cells is often not fully clarified. In this study, we characterized a novel mode of action of the inhibitors MC2580 and DDP-38003 and demonstrated that they trigger myeloid differentiation of AML by down-regulating GSE1 protein, a LSD1 interactor on chromatin. By studying the phenotypic effects of GSE1 depletion in NB4 cells, we observed a strong decrease of cell proliferation in vitro, and of tumour growth in vivo. Comparing the transcriptomic changes induced by GSE1 knock-down with those elicited by LSD1 pharmacological inhibition, we found a common set of genes up-regulated and linked with immune response and cytokine-mediated signalling. Mechanistically, we found that several promoters of these genes are bound by both LSD1 and GSE1 at basal state and that GSE1 binding is strongly reduced upon LSD1 inhibition, as a consequence of its reduced expression. By describing for the first time that LSD1-GSE1 interaction on chromatin enforces the silencing of genes linked to myeloid differentiation and by highlighting that this interaction can be overcome by LSD1 inhibitors, our study offers a new perspective on the use of these compounds to trigger differentiation in leukaemia through GSE1 modulation.
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| Overall design |
ChIP-seq profiling of a V5-tagged isoform of GSE1 transduced in NB4 cells and treated for 24h with the LSD1 inhibitor MC2580 and DMSO as control.
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| Contributor(s) |
Luciano N, Elena C, Fabio B, Tiziana B |
| Citation(s) |
34862459 |
| |
| Submission date |
Jan 11, 2021 |
| Last update date |
Dec 09, 2021 |
| Contact name |
Tiziana Bonaldi |
| E-mail(s) |
tiziana.bonaldi@ieo.it
|
| Organization name |
IEO
|
| Street address |
via Adamello 16
|
| City |
Milan |
| ZIP/Postal code |
20139 |
| Country |
Italy |
| |
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| Platforms (1) |
| GPL9115 |
Illumina Genome Analyzer II (Homo sapiens) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE164560 |
LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin |
|
| Relations |
| BioProject |
PRJNA691202 |
| SRA |
SRP301240 |
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