Effects of LSD1 inhibitors on enhancer functions in T-ALL cells
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ABSTRACT:
PROVIDER: PRJNA492486 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7889980.fastq.gz | Fastqsanger.gz | |||
| SRR7889981.fastq.gz | Fastqsanger.gz | |||
| SRR7889982.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the following subset Series: GSE27714: Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation (expression) GSE27841: Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation (ChIP-seq) Refer to individual Series
2012-01-03 | E-GEOD-27844 | biostudies-arrayexpress
Project description:We treated the T-ALL cell line MOLT4 with a novel LSD inhibitor and performed ChIP-seq analysis using anti-histoneH3K27ac antibody to assess the enhancer function.
2018-09-22 | GSE120314 | GEO
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
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
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 | GSE164553 | GEO
Project description:Transcription factors and chromatin modifiers play important roles in programming and reprogramming of cellular states during development. Much is known about the role of these regulators in gene activation, but relatively little is known about the critical process of enhancer silencing during differentiation. Here we show that the H3K4/K9 histone demethylase LSD1 plays an essential role in decommissioning enhancers during differentiation of embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes critical for control of ESC state. However, LSD1 is not essential for maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to fully differentiate and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At enhancers, LSD1 is a component of the NuRD complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program upon differentiation, which is essential for complete shutdown of the ESC gene expression program and the transition to new cell states. This represents the expression part of the study.
2012-01-03 | E-GEOD-27714 | biostudies-arrayexpress
Project description:Transcription factors and chromatin modifiers play important roles in programming and reprogramming of cellular states during development. Much is known about the role of these regulators in gene activation, but relatively little is known about the critical process of enhancer silencing during differentiation. Here we show that the H3K4/K9 histone demethylase LSD1 plays an essential role in decommissioning enhancers during differentiation of embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes critical for control of ESC state. However, LSD1 is not essential for maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to fully differentiate and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At enhancers, LSD1 is a component of the NuRD complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program upon differentiation, which is essential for complete shutdown of the ESC gene expression program and the transition to new cell states. This is the ChIP-seq part of the study.
2012-01-03 | E-GEOD-27841 | biostudies-arrayexpress
Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Determine the role of LSD1 in androgen signaling.
2014-12-12 | E-GEOD-52201 | biostudies-arrayexpress
Project description:LSD1 inhibitors trigger myeloid differentiation by targeting the LSD1-GSE1 interaction on chromatin
| PRJNA691206 | ENA
Project description:Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by the inevitable development of resistance. A major contributor to resistance is early epigenetic adaptation, leading to persistence of a small number of leukemia cells. Here we show that inhibition of the epigenetic regulator lysine-specific deme-thylase 1 (LSD1) augments the response to inhibitors of the FLT3 kinase in AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cells via proliferative arrest and apoptosis. The drug combination synergistically activates a pro-differentiative epigenetic and transcriptional program while simultaneously suppressing the activity of MYC target genes. High resolution multi-modal epigenetic analyses revealed that combined FLT3 and LSD1 resulted in the suppression of MYC-bound promoters and the activation of PU.1-bound enhanc-ers. Forced expression of MYC partially abrogated the drug effect, and regulon en-richment analysis in primary AML samples nominated STAT5 as a putative regulator of MYC gene expression. STAT5 is highly bound to the MYC blood super-enhancer and inhibition of FLT3 results in a loss of STAT5 binding and a loss of super enhancer acti-vation. Furthermore, knockdown of STAT5 augments LSD1-inhibitor induced cell death. LSD1 inhibition also directly represses MYC target genes which show specific accumulation of the repressive LSD1 substrate H3K9me1. We validated these findings in 67 primary AML samples including 19 FLT3-ITD positive AML samples, with the vast majority demonstrating improved responses with the drug combination. High MYC regulon activity was a predictor of response to the drug combination and RNA-seq on drug treated AML samples revealed suppression of MYC target genes. Finally, single cell ATAC seq on primary AML blasts treated ex-vivo with combined FLT3 and LSD1 inhibition results in a shift from MYC super enhancer-high to a MYC super enhancer-low cell state. Collectively, these studies provide preclinical rationale for the investiga-tion of dual FLT3 and LSD1 inhibition in clinical trial.
2024-03-21 | GSE190785 | GEO