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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Differential gene expression profiling by LSD1 inhibition using novel LSD1 inhibitors (NCD25 and NCD38)

ABSTRACT: LSD1 is a demethylase of histone modification H3k4me1 and H3K4me2. We have developed novel LSD1 inhibitors (NCD25 and NCD38) and found that they are effective to myelodysplastic syndromes and leukemia cells. To understand what mechanisms are affected by these compounds, we employed gene expression profiling analyses. Gene expression profiling data were obtained from HEL, MDS-L, or CMK11-5 cells treated with DMSO (control), NCD25, or NCD38 and compared each other. Expression of eleven transcriptional factors (GFI1, CEBPA, SPI1, MNDA, TAL1, GATA1, NFE2, RXRA, HOXA9, GATA2, and PBX1) was reconfirmed by q-PCR with the same samples. Gene expression of leukemia cells was measured after 48 hours incubation with or without LSD1 inhibitors. Five independent experiments were performed using 3 cell lines (HEL, MDS-L and CMK11-5) and 2 drugs (NCD38 and NCD25).

ORGANISM(S): Homo sapiens

SUBMITTER: Masahiro Kawahara

PROVIDER: E-GEOD-68348 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Differential gene expression profiling by LSD1 inhibition using novel LSD1 inhibitors (NCD25 and NCD38)

Project description:LSD1 is a demethylase of histone modification H3k4me1 and H3K4me2. We have developed novel LSD1 inhibitors (NCD25 and NCD38) and found that they are effective to myelodysplastic syndromes and leukemia cells. To understand what mechanisms are affected by these compounds, we employed gene expression profiling analyses. Gene expression profiling data were obtained from HEL, MDS-L, or CMK11-5 cells treated with DMSO (control), NCD25, or NCD38 and compared each other. Expression of eleven transcriptional factors (GFI1, CEBPA, SPI1, MNDA, TAL1, GATA1, NFE2, RXRA, HOXA9, GATA2, and PBX1) was reconfirmed by q-PCR with the same samples.

2015-04-29 | GSE68348 | GEO

PolyA RNA sequencing of HEL human erythroleukemia cell line under LSD1 inhibition

Project description:To understand the role of LSD1 in transcriptional regulation, RNA-seq analyses of LSD1-inhibited HEL cells were carried out. Cells were collected after the introduction of lentiviral LSD1 shRNA or the treatment with a specific LSD1 inhibitor, S2101. We found that LSD1 inhibition led to decreased expression of genes involved in various metabolic pathways.

2021-05-04 | GSE145397 | GEO

Effect of LSD1 knockdown on histone H3K4 methylation in HEL human erythroleukemia cell line.

Project description:To understand the role of LSD1 in regulating histone H3K4 methylation status, ChIP-seq analyse of mono- and di-methylated H3K4 in LSD1-KD HEL cells were performed. The analyses revealed demethylation of H3K4me1 and H3K4me2 by LSD1 at regulatory regions including CEBPA gene enhancer.

2021-05-04 | GSE145399 | GEO

Genome-wide occupancy of LSD1 in HEL human erythroleukemia cell line.

Project description:We examined the genome-wide distribution of LSD1 bound regions in HEL cells bya ChIP-seq analysis. We found that GATA family transcription factors co-operate with LSD1 to regulate metabolic genes. We also found that LSD1 binds to and represses CEBPA gene enhancer, resulting in the suppression of myeloid cell properties.

2021-05-04 | GSE145401 | GEO

LSD1 Prevents Aberrant Heterochromatin Formation in Neurospora crassa

Project description:Heterochromatin is a specialized form of chromatin that restricts access to DNA and inhibits genetic processes, including transcription and recombination. In Neurospora crassa, constitutive heterochromatin is characterized by trimethylation of lysine 9 on histone H3, hypoacetylation of histones, and DNA methylation. Here we explore whether the conserved histone demethylase, lysine-specific demethylase 1 (LSD1), regulates heterochromatin in Neurospora, and if so, how. Though LSD1 is implicated in heterochromatin regulation, its function is inconsistent across different systems; orthologs of LSD1 have been shown to either promote or antagonize heterochromatin expansion by removing H3K4me or H3K9me respectively. We identify three members of the Neurospora LSD complex (LSDC): LSD1, PHF1, and BDP-1, and strains deficient for any exhibit variable spreading of heterochromatin and establishment of new heterochromatin domains dispersed across the genome. Heterochromatin establishment outside of canonical domains in Neurospora share the unusual characteristic of DNA methylation-dependent H3K9me3; typically, H3K9me3 establishment is independent of DNA methylation. Consistent with this, the hyper-H3K9me3 phenotype of LSD1 knock-out strains is dependent on the presence of DNA methylation, as well as HCHC-mediated histone deacetylation, suggesting spreading is dependent on some feedback mechanism. Altogether, our results suggest LSD1 works in opposition to HCHC to maintain proper heterochromatin boundaries.

2021-07-21 | PXD017300 | Pride

Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation

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

Differential gene expression profiling by deletion of GFI1 super-enhancer (GFI1-SE-KO) upon treatment of a LSD1 inhibitor NCD38 in HEL cells

Project description:Activation of GFI1-super-enhancer (GFI1-SE) by a LSD1 inhibitor NCD38 was relevant to myeloid differentiation and antileukemia effect in human erythroleukemia cells (HEL cells). Thus, we investigated the role of GFI1-SE upon NCD38 treatment in HEL cells. We established three independent sublines with bi-allelic deletion of GFI1-SE (CCE2 #114, #141, and #216) using CRISPR-Cas9 genome editing system in HEL cells and a classical limiting dilution method. Control sublines (Ctrl C1, C2, and C5) were established by transfection of parent vector and limiting dilution. After treatment of each subline with DMSO or NCD38 (LSD1i) for 24 hours, these gene expression profiling data were obtained.

2020-03-31 | GSE128400 | GEO

Effect of LSD1 inhibition on differentiating C2C12 myoblasts

Project description:Analysis of differentiating C2C12 myoblasts treated with two LSD1 specific inhibitors. We found LSD1 is an important regulator of oxidative phenotypes in skeletal muscle cells. Results provide insight into the molecular mechanisms underlying roles of LSD1 in myocytes.

2018-03-19 | GSE86524 | GEO

LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.

2020-11-03 | PXD020590 | Pride

LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin [RNA-seq]

Project description: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.

2021-12-01 | GSE164559 | GEO

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