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Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [ATAC-Seq]

ABSTRACT: To identify regions of genome accessibility influenced by LSD1 inhibition, THP1 AML cells were subjected to ATAC sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90770 | GEO | 2018/03/27

REPOSITORIES: GEO

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Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [anti-LSD1, MYB, and GFI1 ChIP-Seq]

Project description:To identify genomic binding regions, THP1 AML cells were subjected to ChIP sequencing (ChIPseq) using anti-LSD1, MYB or GFI1 antibodies.

2018-03-27 | GSE90769 | GEO

Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [RNA-Seq experiments]

Project description:To determine whether changes in histone modifications directly correlate with changes in transcription, THP1 AML cells were treated with a potent and selective LSD1 inhibitor (OG86) and then subjected to concomitant RNA sequencing (RNAseq) and ChIP sequencing (ChIPseq) for monomethyl-, dimethyl- and trimethyl histone H3 modifications.

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Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [ChIP-Seq: histone modifications]

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Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [anti-H3K9 ac, anti-H3K27, RCOR1, SPI1, and MLL4 ChIP-Seq]

Project description:To determine whether changes in histone modifications directly correlate with changes in transcription, THP1 AML cells were treated with a potent and selective LSD1 inhibitor (OG86, 250nM) and then subjected to concomitant RNA sequencing (RNAseq) and ChIP sequencing (ChIPseq) for histone acetylation modifications, RCOR1, SPI1 and MLL4.

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Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia

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

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Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia

Project description:Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia

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Expression data from THP1-wt and THP1-NTR+ cells with LSD1 inhibitor (OG86), Nitroreductase NfsB (NTR) prodrug and negative control

Project description:The Nitroreductase NfsB (NTR) prodrug of an LSD1 inhibitor is inactive in wild-type THP1 cells, but the prodrug gets activated in the LSD1 inhibitor by the NTR in NTR-expressing THP1 cells (THP1-NTR+). Cell-type specific inhibition of LSD1 in THP1-NTR+ cells with a NTR prodrug is shown with the expression data of the two cell lines, THP1-wt and THP1-NTR+. Data for the LSD1 inhibitor and a negative control with both cell lines are included.

2020-08-04 | GSE155640 | GEO

LSD1 Performs Demethylase-Independent and Context-Specific Roles in Ewing Sarcoma

Project description:Lysine specific demethylase 1 (LSD1), encoded by the gene KDM1A, is overexpressed and correlates with poor patient prognosis in Ewing sarcoma. LSD1 colocalizes with the FET-fusion (EWSR::FLI1, EWS::ERG, etc) throughout the genome and has therefore been considered a critical co-regulator driving the progression of Ewing sarcoma. However therapeutic targeting of LSD1 by irreversible and noncompetitive inhibitors has yielded mixed results. Irreversible, enzymatic inhibition seems ineffective, but reversible noncompetitive inhibition has predominant off target mechanisms, leaving open the question of LSD1 function in Ewing sarcoma. Here we take a robust approach through multiple methods of depletion in multiple cell lines to define LSD1 function, both enzymatic and nonenzymatic, in Ewing sarcoma cell lines. We define a core set of 22 genes that are commonly repressed by LSD1 in all cell lines and that repression of these genes downregulates synapse functioning and e-cadherin target genes. De-repression of these genes with LSD1 loss is an early and sustained genotype in all cell lines tested. Furthermore, we define distinct gene sets in each cell line that are regulated by the enzymatic and nonenzymatic functions of LSD1 and find repression of e-cadherin target genes to be nonenzymatically regulated. This finding supports the growing body of evidence that in addition to their canonical catalytic activity, enzymes serve essential noncanonical roles as well. Lastly, we uncovered evidence through use of the irreversible inhibitor OG-L002 that 2D cytotoxicity and proliferation assays may be insufficient to determine how Ewing sarcoma responds to LSD1 inhibition.

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Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition [RNA-seq]

Project description:Metazoan enhancers are decorated by mono-methylation (me1) of the lysine 4 residue on histone H3 (H3K4), a mark deposited by methyltransferases MLL3/MLL4 and removed by the lysine-specific histone demethylase 1A (LSD1 or KDM1A) via its flavin adenine dinucleotide (FAD)-dependent amine oxidase activity. As a component of histone deacetylases HDAC1/2-containing complex CoREST, LSD1 is required for animal development, and is implicated in Kabuki Syndrome-like congenital diseases and multiple types of cancer. Although prior research has investigated the demethylase function of LSD1 extensively, the mechanisms underlying LSD1’s role in development and diseases remain enigmatic. Here, we have utilized genetic, epigenetic, genomic, and cell biology approaches to dissect the role of LSD1 and its demethylase activity in gene regulation and cell fate transition. Surprisingly, the catalytic inactivation of LSD1 only has a mild impact on gene expression whereas the loss of LSD1 protein de-represses enhancers globally. Moreover, LSD1 deletion, rather than its catalytic inactivation, causes defects in spontaneous differentiation, the transition from naive to primed pluripotency, embryoid body formation, and cardiomyocyte differentiation. Interestingly, deletion of LSD1 increases H3K27ac levels and binding of P300 to LSD1-targeted enhancers. We further show that the gain in the level of H3K27ac catalyzed by P300/CBP, not the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss. Taken together, our study demonstrates a demethylase-independent role of LSD1 in regulating enhancers and cell fate transition, providing insight into the treatment of diseases driven by LSD1 mutations and misregulation.

2023-07-06 | GSE232252 | GEO

Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition [ChIP-seq]

2023-07-06 | GSE232250 | GEO