The application of ChIP-seq to study LSD1 and hematopoietic TF binding on enhancers upon LSD1 inhibition.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE231736 | GEO | 2024/05/04
REPOSITORIES: GEO
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Project description:The application of ChIP-seq to study LSD1 and hematopoietic TF binding on enhancers upon LSD1 inhibition.
| PRJNA967458 | ENA
Project description:Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cancer cell survival, including in prostate cancer. LSD1 has been shown to perfrom catalytic independent function sto promote prostate cancer survival. Here, we tested the levels of LSD1's canonical target H3K4me2 upon LSD1 inhibition with SP2509 across the genome using CUT and RUN analysis.
2023-08-30 | GSE235211 | GEO
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.
2020-09-04 | GSE148103 | GEO
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.
2020-09-04 | GSE147814 | GEO
Project description:Transcriptional coregulators and transcription factors (TFs) contain intrinsically disordered regions (IDRs) that are critical for their partitioning and function in gene regulation. Canonically, IDRs drive coregulator-TF association by directly promoting multivalent protein-protein interactions. Using a chemical genetic approach, we report an unexpected mechanism by which the IDR of the corepressor LSD1 excludes TF association, acting as a dynamic conformational switch that tunes repression of active cis-regulatory elements. Hydrogen-deuterium exchange shows that the LSD1 IDR interconverts between transient open and closed conformational states, the latter of which inhibits partitioning of the proteins structured domains with TF hubs. This autoinhibitory switch controls leukemic differentiation by modulating repression of active cis-regulatory elements bound by LSD1 and master hematopoietic TFs. Together, these studies unveil that the dynamic crosstalk between opposing structured and unstructured regions is an alternative paradigm by which disordered regions can shape coregulator-transcription factor interactions to control cis-regulatory landscapes and cell fate.
2024-03-05 | MSV000094239 | MassIVE
Project description:Enhancer reactivation and pluripotency gene (PpG) expression could induce stemness and enhance tumorigenicity in cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1–mediated H3K4me1 demethylation followed by DNA methylation. Here, we observed a widespread retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. The absence of H3K4me1 demethylation could not be rescued by Lsd1 overexpression. Based on the observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Lsd1-Oct4 interaction affects Lsd1 catalytic activity. Our data show a dose-dependent inhibition of Lsd1 by Oct4 in vitro and retention of H3K4me1 at PpGe post-differentiation in Oct4 overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells may establish a primed enhancer state that is susceptible to reactivation leading to aberrant PpG expression.
2020-06-29 | GSE135225 | GEO
Project description:Enhancer reactivation and pluripotency gene (PpG) expression could induce stemness and enhance tumorigenicity in cancer stem cells. Silencing of PpG enhancers (PpGe) during embryonic stem cell differentiation involves Lsd1–mediated H3K4me1 demethylation followed by DNA methylation. Here, we observed a widespread retention of H3K4me1 and DNA hypomethylation at PpGe associated with a partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post-differentiation. The absence of H3K4me1 demethylation could not be rescued by Lsd1 overexpression. Based on the observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Lsd1-Oct4 interaction affects Lsd1 catalytic activity. Our data show a dose-dependent inhibition of Lsd1 by Oct4 in vitro and retention of H3K4me1 at PpGe post-differentiation in Oct4 overexpressing P19 ECCs. These data suggest that Lsd1-Oct4 interaction in cancer stem cells may establish a primed enhancer state that is susceptible to reactivation leading to aberrant PpG expression.
2020-06-29 | GSE135226 | 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: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
Project description:We performed sequencing of Nuclear RNA from Lsd1-WT, Lsd1-GT, KDM5c-WT, and KDM5C-KO mouse embryonic stem cells (mES). We also performed sequencing of Total RNA from Lsd1-WT and Lsd1-GT mES.
2020-09-01 | GSE94556 | GEO