Gene expression changes upon drug withdrawal (Mel888 cell line)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE98867 | GEO | 2017/08/09
SECONDARY ACCESSION(S): PRJNA386528
REPOSITORIES: GEO
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Project description:In this study we investigate the mechanism of drug addiction
2017-08-09 | GSE98866 | GEO
Project description:Gene expression changes upon drug withdrawal
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Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-09 | GSE98868 | GEO
Project description:BackgroundTumors are characterized by global changes in epigenetic changes such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as Vorinostatis and DNA methyltransferase inhibitors (DNMTi) such as Zebularine. However, a fundamental challenge with such approaches is the lack of genomic specificity, i.e., the transcriptional changes at different genomic loci can be highly variable thus making it difficult to predict the consequences on the global transcriptome and drug response. For instance, treatment with DNMTi may upregulate the expression of not only a tumor suppressor but also an oncogene leading to unintended adverse effect.MethodsGiven the pre-treatment transcriptome and epigenomic profile of a sample, we assessed the extent of predictability of locus-specific changes in gene expression upon treatment with HDACi using machine learning.ResultsWe found that in two cell lines (HCT116 treated with Largazole at 8 doses and RH4 treated with Entinostat at 1μM) where the appropriate data (pre-treatment transcriptome and epigenome as well as post-treatment transcriptome) is available, our model distinguished the post-treatment up versus downregulated genes with high accuracy (up to ROC of 0.89). Furthermore, a model trained on one cell line is applicable to another cell line suggesting generalizability of the model.ConclusionsHere we present a first assessment of the predictability of genome-wide transcriptomic changes upon treatment with HDACi. Lack of appropriate omics data from clinical trials of epigenetic drugs currently hampers the assessment of applicability of our approach in clinical setting.
| S-EPMC10541107 | biostudies-literature
Project description:The investigators aim to assess the procedure time and miss rate of polyps when performing polypectomy in the colon on the way up* and down** or only on the way down**.
(* advancing the scope to the cecum, ** pulling back the scope after intubation of the cecum). Our hypothesis is that using the strategy to remove all visible polyps firstly on the way up and secondly on the way down is less time consuming and misses less polyps as with the strategy to remove polyps only on the way down.
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Project description:Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant BRAF MUT or NRAS MUT melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal–induced pERK rebound upregulated p38–FRA1–JUNB–CDKN1A and downregulated proliferation, but only a robust pERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi addiction across the board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos related cell death. Specifically in MEKi-resistant NRAS MUT or atypical BRAF MUT melanoma, treatment with a type I RAF inhibitor intensified pERK rebound elicited by MEKi withdrawal, thereby promoting a cell death–predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi addiction.
2017-11-28 | GSE87326 | GEO
Project description:Substance abuse and addiction represent a major public health problem that impacts multiple dimensions of society, including healthcare, economy, and workforce. In 2021, over 100,000 drug overdose deaths have been reported in the US with an alarming increase in fatalities related to opioids and psychostimulants. Understanding of the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating in total over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bona-fide enhancers and highlighted the KLF/SP1, RFX and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls, identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.
2022-05-11 | GSE193757 | GEO
Project description:Retrograde signaling induced remodelling of nuclear gene expression from mitochondrial ribosomal dysfunction was analyzed. Global expression profile changes in mouse embryonic fibroblasts were assesed under actinonin treatment 6, 24, 48 and 72 hours post drug addiction. Control and four different time points with two labels and two replicates each
2013-07-05 | E-GEOD-44109 | biostudies-arrayexpress
Project description:Heroin addiction and withdrawal influence multiple physiological functions including immune responses, but the mechanism remains largely elusive. The objective of this study was to investigate the immune system function and molecular inflammatory interactome particularly the cytokines and RNA regulatory network in heroin addicts undergoing withdrawal compared healthy controls.
2021-07-03 | GSE172306 | GEO
Project description:Retrograde signaling induced remodelling of nuclear gene expression from mitochondrial ribosomal dysfunction was analyzed. Global expression profile changes in mouse embryonic fibroblasts were assesed under actinonin treatment 6, 24, 48 and 72 hours post drug addiction.
2013-07-05 | GSE44109 | GEO