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Proteasome inhibition reprograms chromatin landscape in breast cancer (Start-Seq)

ABSTRACT: The 26S proteasome regulates general protein homeostasis and controls vital cellular processes, including cell division and transcriptional regulation. Cancer cells are dependent on the proper functioning of the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibition has emerged as an effective therapeutic strategy, although mechanisms by which this approach achieves its outcomes remain unclear. We performed an integrative analysis of the transcriptome and chromatin landscape of MCF-7 breast cancer cells treated with a model proteasome inhibitor, MG132, to examine the consequences of proteasome inhibition on gene regulation. MG132 treatment initiated dynamic changes in chromatin accessibility at specific loci termed Differentially Open Chromatin Regions (DOCRs). DOCRs with increased accessibility were primarily distal to transcription start sites (TSS), while those with decreased accessibility were promoter proximal and distal to TSS. Promoter proximal DOCRs showed a unique chromatin architecture associated with distinct divergent transcription patterns. Conversely, DOCRs distal to TSS were enriched in oncogenic super enhancers that are predominantly accessible in non-basal compared to basal breast tumor subtypes. These data define distinct chromatin states and RNAPII transcription patterns, revealing molecular mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241599 | GEO | 2024/03/13

REPOSITORIES: GEO

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Proteasome inhibition reprograms chromatin landscape in breast cancer (RNA-Seq)

Project description:The 26S proteasome regulates general protein homeostasis and controls vital cellular processes, including cell division and transcriptional regulation. Cancer cells are dependent on the proper functioning of the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibition has emerged as an effective therapeutic strategy, although mechanisms by which this approach achieves its outcomes remain unclear. We performed an integrative analysis of the transcriptome and chromatin landscape of MCF-7 breast cancer cells treated with a model proteasome inhibitor, MG132, to examine the consequences of proteasome inhibition on gene regulation. MG132 treatment initiated dynamic changes in chromatin accessibility at specific loci termed Differentially Open Chromatin Regions (DOCRs). DOCRs with increased accessibility were primarily distal to transcription start sites (TSS), while those with decreased accessibility were promoter proximal and distal to TSS. Promoter proximal DOCRs showed a unique chromatin architecture associated with distinct divergent transcription patterns. Conversely, DOCRs distal to TSS were enriched in oncogenic super enhancers that are predominantly accessible in non-basal compared to basal breast tumor subtypes. These data define distinct chromatin states and RNAPII transcription patterns, revealing molecular mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology.

2024-03-13 | GSE241600 | GEO

Proteasome inhibition reprograms chromatin landscape in breast cancer (ChIP-Seq)

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Proteasome inhibition reprograms chromatin landscape in breast cancer (ATAc-Seq)

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Transcriptional regulation in MCF-7 breast cancer cells treated with proteasome inhibitor MG132 [rna_polii_chIP-seq]

Project description:We report whole genome chromatin immunoprecipitation followed by sequencing (ChIP-seq) of 3 different RNA Pol II CTD modifications in MCF-7 breast cancer cells treated with vehicle (UNTR) or the proteasome inhibitor MG132 for 4 (MG4H) or 24 (MG24H) hours. We find the non-phosphorylated form of RNA Pol II CTD accumulates at TSS of all expressed genes in proteasome inhibited cells, particularly after 24H of MG132 treatment. Proteasome inhibition enhances Ser5-P and Ser2-P binding at TSS of genes induced by MG132. We note that proteasome inhibition establishes unique Ser2-P 5’ to 3’ gene profiles at induced compared to repressed genes. Overall proteasome inhibition enhances RNA Pol II processivity and expression of gene networks relevant to breast cancer. The study provides a comprehensive resource of RNA Pol II binding in proteasome inhibited cells.

2020-01-07 | GSE142010 | GEO

Chromatin state of MCF-7 breast cancer cells treated with proteasome inhibitor MG132 [histone_mod_chip_seq]

Project description:We report whole genome chromatin immunoprecipitation followed by sequencing (ChIP-seq) of histone modifications in MCF-7 breast cancer cells treated with vehicle (UNTR) or the proteasome inhibitor MG132 for 4 (MG4H) or 24 (MG24H) hours. We find that MG132 treatment results in the spreading of the H3-trimethyl lysine 4 mark into gene bodies of a subset of induced genes in MCF-7 cells. The spreading of the H3K4me3 is concomitant with hyperacetylation (H3K27ac, K122ac and K9/14ac) of the corresponding gene TSS. H3 Lysine 36 trimethylation mark is enriched at genes that are induced by MG132. Finally, we show that proteasome inhibition establishes a chromatin state that enhances antiproliferative, while dampening cell proliferative gene expression programs relevant to breast cancer. The study provides a comprehensive resource of histone modifications in proteasome inhibited cells.

2020-01-07 | GSE142009 | GEO

Alteration of mRNA expression in breast cancer cells upon chemical inhibition of the 26S proteasome

Project description:The 26S proteasome regulates degradation of many cellular proteins to maintain cellular homeostasis. Disruption of proteasome activity followed by dysregulation of tumor suppressors and oncogenes is rampant in many cancers, hence chemical inhibitors of the proteasome have utility as cancer therapeutics, although the underlying mechanisms of their effects in the clinic is poorly understood. We have employed whole genome microarray expression profiling as a discovery platform to identify genes and potential signaling pathways that are affected MCF7 breast cancer cells are treated with MG132 a chemical inhibitor of the proteasome. Total RNA was collected from MCF7 breast cancer cells treated with DMSO (vehicle control) and 1 uM MG132 for 4 or 24H . We identified time dependent changes in the expression of genes enriched in p53 and estrogen receptor pathways, two signatures relevant to breast cancer biology.

2020-01-07 | GSE141858 | GEO

Transcription profiling of human MCF-7 cells treated with proteasome inhibitor MG132 and either dexamethasone or 17b-estradiol

Project description:The objective of the study was to investigate the effect of proteasome inhibition on glucocorticoid and estrogen receptor regulated gene expression. Experiment Overall Design: MCF-7 cells were treated with proteasome inhibitor (MG132), dexamethasone, 17b-estradiol or MG132 plus dexamethasone or MG132 plus 7b-estardiol. Control cells were not treated. RNA was collected from 2 biological experiments.

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Chromatin state of MCF-7 breast cancer cells treated with proteasome inhibitor MG132 [histone_mod_chip_seq]

Project description:Chromatin state of MCF-7 breast cancer cells treated with proteasome inhibitor MG132 [histone_mod_chip_seq]

| PRJNA595567 | ENA

Chromatin-informed inference of transcriptional programs in gynecologic cancers [ATAC-Seq]

Project description:Epigenomic data on transcription factor occupancy and chromatin accessibility can elucidate the developmental origin of cancer cells and reveal the enhancer landscape of key oncogenic transcriptional regulators. However, in many cancers, epigenomic analyses have been limited, and computational methods to infer regulatory networks in tumors typically use expression data alone, or rely on transcription factor (TF) motifs in annotated promoter regions. Here, we develop a novel machine learning strategy called PSIONIC (patient-specific inference of networks informed by chromatin) to combine cell line chromatin accessibility data with large tumor expression data sets and model the effect of enhancers on transcriptional programs in multiple cancers. We generated a new ATAC-seq data set profiling chromatin accessibility in gynecologic and basal breast cancer cell lines and applied PSIONIC to 723 RNA-seq experiments from ovarian, uterine, and basal breast tumors as well as 96 cell line RNA-seq profiles. Our computational framework enables us to share information across tumors to learn patient-specific inferred TF activities, revealing regulatory differences between and within tumor types. Many of the identified TF regulators were significantly associated with survival outcome in basal breast, uterine serous and endometrioid carcinomas. Moreover, PSIONIC-predicted activity for MTF1 in cell line models correlated with sensitivity to MTF1 inhibition. Therefore computationally dissecting the role of TFs in gynecologic cancers may ultimately advance personalized therapy.

2019-05-01 | GSE114964 | GEO

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