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Proteasome inhibition silences oncogenic transcripts in multiple myeloma through HDAC3-mediated DNA condensation and gene relocation [CUT&RUN]

ABSTRACT: This study provides a genome-wide map of changes in degradative ubiquitination in response to proteasome inhibition in the multiple myeloma cell line MM.1S. Following proteasome inhibition with lactacystin, CUT and RUN assays were carried out to determine the genomic locations of ubiquitin in multiple myeloma cells stably expressing a flagged version of ubiquitin (MM.1S-3XFlag Ubiquitin cells). In addition, we report the DNA binding locations of the transcription factor c-MYC in basal conditions in MM.1S parental cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193302 | GEO | 2022/11/21

REPOSITORIES: GEO

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Proteasome inhibition silences oncogenic transcripts in multiple myeloma through HDAC3-mediated DNA condensation and gene relocation [RNA-seq]

Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.

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Proteasome inhibition silences oncogenic transcripts in multiple myeloma through HDAC3-mediated DNA condensation and gene relocation [ChIP-seq]

Project description:This study provides a genome-wide map of changes in histone mark modifications and HDAC3 binding in response to protesome inhibition in the multiple myeloma cell line MM.1S. Chromatin immunoprecipitation assays were carried out to determine the genomic locations of histone modifications (H3K27ac, H3K4me1, H3K4me3) and histone deacetylase 3 (HDAC3) binding locations in multiple myeloma cells following proteasome inhibition with either lactacystin, bortezomib or carfilzomib. In addition, we report the effects of the overexpression of the E3-ubiquitin ligase Siah2 and the impact of HDAC3 knockdown on H3K27 acetylation levels in multiple myeloma cells treated with lactacystin. Our global ChIP-seq analysis of histone marks showed that enhancer and promoter marks (H3K4me1 and H3K4me3, respectively) present little response to proteasome inhibition, while the acetylation of histone H3K27 was significantly up- or down-regulated after three-hour treatment with proteasome inhibitors. Treatment of the cells with lactacystin, bortezomib or carfilzomib strongly increased HDAC3 recruitment at cell cycle and mitochondrial promoters, indicating that proteasome inhibition stabilized HDAC3 locally at the promoter of these genes to induce their repression. Furthermore, genome-wide ChIP-seq analysis of H3K27ac profiles showed that overexpression of Siah2 enhanced H3K27 acetylation levels at cell cycle and mitochondrial promoters.

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Project description:Purpose: We report the NGS-derived transcriptome profiling (paired-end RNA-seq) following proteasome inhibition in the multiple myeloma cell line MM.1S. Methods: MM.1S cells were treated for six hours with the synthetic proteasome inhibitor lactacystin or clinically-approved proteasome inhibitor bortezomib and RNA expression changes were quantified and compared to DMSO control-treated cells by RNA-sequencing.

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Gene expression profiles of myeloma cells treated with NAE inhibitor

Project description:The transcriptional profile of the human multiple myeloma (MM) cell line MM.1S treated with MLN4924 vs control MM.1S cells was characterized by oligonucleotide microarray analysis, using the human U133 plus 2.0 Affymetrix GeneChip, according to previously described protocols for total RNA extraction and purification; cDNA synthesis; in vitro transcription reaction for production of biotin-labeled cRNA; hybridization of cRNA with U133plus2.0 Affymetrix gene chips; and scanning of image output files. Scanned image output files were analyzed using DNA-Chip Analyzer (dChip) (www.dchip.org), including conversion to DCP files, normalization and modeling. The gene expression profile of MM.1S cells for each time point of MLN4924 treatment was compared to the profile of control MM.1S cells. The NEDD8 activating enzyme (NAE) is upstream of the 20S proteasome in the ubiquitin/proteasome pathway and catalyzes the first step in the neddylation pathway. NEDD8 modification of cullins is required for ubiquitination of cullin-ring ligases (CRLs), which regulate degradation of a distinct subset of proteins. The more targeted impact of NAE on protein degradation prompted us to study MLN4924, an investigational NAE inhibitor, in preclinical multiple myeloma (MM) models. In vitro treatment with MLN4924 led to dose-dependent decrease of viability in a panel of human MM cell lines. In this analysis, we evaluated the molecular changes triggered in MM.1S myeloma cells by their in vitro treatment with MLN4924. The transcriptional profiles of each experimental condition were characterized by oligonucleotide microarray analysis, using the human U133 plus 2.0 Affymetrix GeneChip. The human multiple myeloma (MM) cells MM.1S were cultured in vitro in the presence or absence of the NEDD8 activating enzyme (NAE) inhibitor MLN4924 for 8, 16 or 24hrs. The gene expression profiles of drug treated cells were compared with the profiles of control MM.1S cells.

2012-05-01 | E-GEOD-33577 | biostudies-arrayexpress

Gene expression profiles of myeloma cells treated with NAE inhibitor

2012-05-02 | GSE33577 | GEO

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2007-04-09 | GSE6980 | GEO

Transcriptomic signature induced in bone marrow Mesenchymal Stromal Cells (MSC) after interaction with malignant multiple myeloma cells: implications in myeloma progression.

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2015-06-30 | E-GEOD-68259 | biostudies-arrayexpress

Illumina Infinium whole-genome SNP-CN data from cell lines originating from patients with multiple myeloma

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2015-06-30 | E-GEOD-68258 | biostudies-arrayexpress

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