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LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [inhibitors]

ABSTRACT: LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [inhibitors]

PROVIDER: PRJNA552362 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9636810.fastq.gz	Fastqsanger.gz
	SRR9636820.fastq.gz	Fastqsanger.gz
	SRR9636830.fastq.gz	Fastqsanger.gz
	SRR9636840.fastq.gz	Fastqsanger.gz
	SRR9636850.fastq.gz	Fastqsanger.gz

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LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors

Project description:LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors

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LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [ChIP-seq]

Project description:LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [ChIP-seq]

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LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [proliferation vs differentiation]

Project description:LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [proliferation vs differentiation]

| PRJNA552360 | ENA

LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [inhibitors]

Project description:We report the impact of the pharmacological inhibition of the Histone 3 Lysine 4 demethylase (H3K4) LSD1 (KDM1A) enzymatic activity on genome-wide gene expression in normal human epidermal keratinocyte (NHEK)

2019-08-20 | GSE133737 | GEO

LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors.

Project description:Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1's role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.

| S-EPMC6719800 | biostudies-literature

LSD1 inhibition promotes epithelial differentiation through derepression of fate- determining transcription factors [ChIP-seq]

Project description:We report the impact of the pharmacological inhibition of the Histone 3 Lysine 4 demethylase (H3K4) LSD1 (KDM1A) enzymatic activity on its binding genome wide and how it impacts genome-wide H3K4me1 and H3K4me2 deposition in Normal Human Epidermal Keratinocytes (NHEK)

2019-08-20 | GSE133560 | GEO

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. 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).

2015-04-29 | E-GEOD-68348 | biostudies-arrayexpress

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

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

2021-12-01 | GSE164553 | GEO