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LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1 [ChIP-Seq]

ABSTRACT: We characterized the changes in histone modifications as well as the localization of LSD1 and GFI1B for both wt SET-2 and drug-resistant SET-2 LSD1 (Leu659_Asn660insArg) treated with GSK-LSD1

ORGANISM(S): Homo sapiens

PROVIDER: GSE121424 | GEO | 2019/01/23

REPOSITORIES: GEO

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LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1 [RNA-Seq]

Project description:We characterized the effect of GSK-LSD1 treatment on gene expression for both wt SET-2 and drug-resistant SET-2 LSD1 (Leu659_Asn660insArg)

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LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1

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GFI1B and LSD1 repress myeloid traits during megakaryocyte differentiation

Project description:The transcription factor Growth Factor Independence 1B (GFI1B) recruits Lysine Specific Demethylase 1A (LSD1/KDM1A) to stimulate gene programs relevant for megakaryocyte and platelet biology. Inherited pathogenic GFI1B variants result in thrombocytopenia and bleeding propensities with varying intensity. Whether these affect similar gene programs is unknow. Here we studied transcriptomic effects of four patient-derived GFI1B variants (GFI1BT174N,H181Y,R184P,Q287*) in MEG01 megakaryoblasts. Compared to normal GFI1B, each variant affected different gene programs with GFI1BQ287* uniquely failing to repress myeloid traits. In line with this, single cell RNA-sequencing of induced pluripotent stem cell (iPSC)-derived megakaryocytes revealed a 4.5-fold decrease in the megakaryocyte/myeloid cell ratio in GFI1BQ287* versus normal conditions. Inhibiting the GFI1B-LSD1 interaction with small molecule GSK-LSD1 resulted in activation of myeloid genes in normal iPSC-derived megakaryocytes similar as observed for GFI1BQ287* iPSC-derived megakaryocytes. Thus, GFI1B and LSD1 facilitate gene programs relevant for megakaryopoiesis while simultaneously repressing programs that induce myeloid differentiation.

2024-03-28 | PXD050401 | Pride

LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1 [ChIP-Seq]

Project description:LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1 [ChIP-Seq]

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LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1 [RNA-Seq]

Project description:LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1 [RNA-Seq]

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Human small intestinal organoids grown with a specific protocol to enrich for Paneth cells were treated with an inhbitor (GSK-LSD1) for the epigenetic modulator LSD1.

Project description:To assess the role of LSD1 in human intestinal epithelium, human small intestinal organoids were treated with an inhibitor for LSD1 (GSK-LSD1) and compared to untreated organoids. The organoids were grown with specific conditions where Paneth cells are present in the organoids as similar experiments in mice show that Paneth cells disappear upon GSK-LSD1 treatment. Similar to mouse intestinal organoids, Paneth cells dissappear upon GSK-LSD1 treatment. Furthermore, we used these gene set enrichment analysis on these microarray data to show that these human intestinal organoids have a similar phenotype as mice epithelium without LSD1.

2020-11-16 | E-MTAB-7863 | biostudies-arrayexpress

GFI1B and LSD1 repress myeloid traits during megakaryocyte differentiation

Project description:Mutations in transcription factor Growth Factor Independence 1B (GFI1B) cause inherited bleedings with varying intensity possibly caused by different effects on the transcriptional function of GFI1B. We studied transcriptomic changes of normal and GFI1BT174N,H181Y,R184P,Q287* mutants in megakaryoblast MEG01 cells using RNA-sequencing. Compared to normal GFI1B each variant affected different gene modules with limited overlap between variants. Remarkably, GFI1BQ287* specifically activated a myeloid-associated gene module. Based on this finding we studied megakaryocyte differentiation using normal and GFI1BQ287* patient-derived induced pluripotent stem cells (IPSC) followed by single cell RNA-sequencing. This revealed a 45-fold decrease in the megakaryocyte/myeloid cell ratio in the GFI1BQ287* versus control condition. Moreover, myeloid specific genes were expressed within GFI1BQ287* but not normal megakaryocytes. Finally, we studied how megakaryocyte development was affected by inhibiting binding of GFI1B to Lysine Specific Demethylase 1 (LSD1), an interaction required for megakaryocyte development. Treatment of both MEG01 cells and normal IPSC-derived developing megakaryocytes with the small-molecule inhibitor GSK-LSD1 resulted in profound activation of myeloid gene programs within megakaryocytes, while the IPSC-derived megakaryocyte/myeloid ratio dropped two-fold. We conclude that GFI1B and LSD1 suppress myeloid differentiation allowing for proper megakaryocyte development. LSD1 inhibitor and GFI1BQ287*-mediated perturbation of this function causes myeloid skewing during megakaryocyte development.

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Project description:The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates non-alcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism potentially via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.

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LSD1 pharmacological inhibition in SET-2 containing wild type and mutant LSD1

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-01-23 | GSE121426 | GEO

Effect of GFI1B ectopic expression in the hematopoietic or endothelial commitment of human iPSC derived CD34+CD43-CD73- hemogenic endothelium (HE)

Project description:In this study we focused on unrevealing the role of major transcriptional factor GFI1B and its cofactor, LSD1 in human endothelial to hematopoietic transition (EHT). We applied irreversible LSD1 inhibitor (GSK-LSD1) to healthy iPSC lines. Interestingly, LSD1 inhibited healthy lines which showed complete absence of hematopoietic cell output, did not showed detection of GFI1B expression, suggesting a timed transcriptional program. In order to test this hypothesis, we ectopically expressed GFI1B in the uncommitted HE cells, leading to downregulation of endothelial genes and an upregulation of hematopoietic genes, including GATA2, KIT, RUNX1 and SPI1.

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