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

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

PROVIDER: PRJNA552480 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9622050.fastq.gz	Fastqsanger.gz
	SRR9622060.fastq.gz	Fastqsanger.gz
	SRR9622051.fastq.gz	Fastqsanger.gz
	SRR9622052.fastq.gz	Fastqsanger.gz
	SRR9622053.fastq.gz	Fastqsanger.gz

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

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

| PRJNA552362 | ENA

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]

| PRJNA551890 | ENA

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

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

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

2019-08-20 | GSE133766 | GEO

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

Project description:Genome-wide gene expression changes triggered by Ca2+-induced differentiation of epidermal progenitors

2019-08-20 | GSE133738 | 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

Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition [scRNA-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 | GSE232253 | GEO

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