Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA355867 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5068840_1.fastq.gz | Fastqsanger.gz | |||
| SRR5068840_2.fastq.gz | Fastqsanger.gz | |||
| SRR5068850_1.fastq.gz | Fastqsanger.gz | |||
| SRR5068850_2.fastq.gz | Fastqsanger.gz | |||
| SRR5068841_1.fastq.gz | Fastqsanger.gz |
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Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.
2023-03-11 | PXD030581 | Pride
Project description:Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia
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Project description:The lysine-specific demethylase 1 (LSD1) regulates hematopoietic stem cell differentiation and has been identified as a therapeutic target in hematological disorders. LSD1 demethylates mono and dimethylated histones 3 at lysine 4 and 9. In addition, it acts as a scaffold for the formation of chromatin-modifying complexes that regulates the transcription of myeloid-lineage-specific genes in complex with GFI1, a transcriptional repressor. While both enzymatic and non-enzymatic functions of LSD1 have been well defined, the relative importance of these two functions in hematopoiesis remains incompletely understood. Here, we investigated the contribution of enzymatic and non-enzymatic functions of LSD1 to myelopoiesis. We show that myeloid differentiation is independent of the enzymatic functions of LSD1 but requires the non-enzymatic, scaffolding function, which directs GFI1 binding to target sequences. In absence of the LSD1 protein, GFI1 DNA binding is diminished and myeloid cell differentiation arrests at an immature, myelomonocytic-like cell stage, which overexpresses Prtn3. We provide functional data implicating Prtn3 as an effector of the stem cell expansion and myeloid maturation block caused by the loss of LSD1.
2025-08-12 | GSE286398 | GEO
Project description:The lysine-specific demethylase 1 (LSD1) regulates hematopoietic stem cell differentiation and has been identified as a therapeutic target in hematological disorders. LSD1 demethylates mono and dimethylated histones 3 at lysine 4 and 9. In addition, it acts as a scaffold for the formation of chromatin-modifying complexes that regulates the transcription of myeloid-lineage-specific genes in complex with GFI1, a transcriptional repressor. While both enzymatic and non-enzymatic functions of LSD1 have been well defined, the relative importance of these two functions in hematopoiesis remains incompletely understood. Here, we investigated the contribution of enzymatic and non-enzymatic functions of LSD1 to myelopoiesis. We show that myeloid differentiation is independent of the enzymatic functions of LSD1 but requires the non-enzymatic, scaffolding function, which directs GFI1 binding to target sequences. In absence of the LSD1 protein, GFI1 DNA binding is diminished and myeloid cell differentiation arrests at a granulocyte-macrophage-progenitor-like cell stage, which overexpresses Prtn3. We provide functional data implicating Prtn3 as an effector of the stem cell expansion and myeloid maturation block caused by the loss of LSD1.
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Project description:The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis.
2020-05-26 | PXD012954 | Pride
Project description:Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [ATAC-Seq]
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Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.
2022-10-06 | GSE192974 | GEO
Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.
2022-10-06 | GSE192973 | GEO
Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.
2022-10-06 | GSE192972 | GEO
Project description:Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [RNA-Seq experiments]
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