Long-term treatment with bortezomib induces specific methylation changes in differentiated neuronal cells
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ABSTRACT:
PROVIDER: PRJNA837266 | ENA |
REPOSITORIES: ENA
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Project description:Genome-wide patterns of DNA methylation were quantified using the Illumina Infinium HumanMethylationEPIC BeadChip in DNA samples extracted from LUHMES cell line cells repeatedly treated with bortezomib (BTZ).
2022-08-03 | GSE202792 | GEO
Project description:Bortezomib (BTZ) is proteasome inhibitor, effectively used in the treatment of multiple myeloma, but frequently discontinued due to peripheral neuropathy, which develops in patients after consecutive treatment cycles. The molecular mechanisms affected by BTZ in neuronal cells, which result in neuropathy, remain unknown. However, BTZ is unlikely to lead to permanent morphological nerve damage, because neuropathy reverses after discontinuation of treatment, and nerve cells have very limited renewal capacity. We have previously shown that BTZ induces methylation changes in SH-SY5Y cells, which take part in the development of treatment resistance. Here, we hypothesized that BTZ affects the methylomes of mature neurons, and these changes are associated with BTZ neurotoxicity. Thus, we studied methylomes of neuronal cells, differentiated from the LUHMES cell line, after cycles of treatment with BTZ. Our results show that BTZ induces specific methylation changes in mature neurons, which are not present in SH-SY5Y cells after BTZ treatment. These changes appear to affect genes involved in morphogenesis, neurogenesis, and neurotransmission. Furthermore, identified methylation changes are significantly enriched within binding sites of transcription factors previously linked to neuron physiology, including EBF, PAX, DLX, LHX, and HNF family members. Altogether, our results indicate that methylation changes are likely to be involved in BTZ neurotoxicity.
| S-EPMC9319119 | biostudies-literature
Project description:Primary effusion lymphoma is an aggressive B-cell lymphoma most commonly diagnosed in HIV-positive patients and universally associated with Kaposi’s sarcoma-associated herpesvirus (KSHV). Chemotherapy treatment of PEL yields only short-term remissions in the vast majority of patients yet efforts to develop superior therapeutic approaches have been impeded by lack of animal models that more accurately mimic human disease. To address this issue we developed a direct xenograft model, UM-PEL-1, by transferring freshly-isolated human PEL cells into the peritoneal cavities of NOD/SCID mice without in vitro cell growth. We utilized this model to show that bortezomib induces PEL remission and extends overall survival of mice bearing lymphomatous effusions. Transcriptome analysis by genomic arrays revealed that bortezomib downregulated cell cycle progression, DNA replication, and Myc-target genes. The microarray analysis was conducted on mice bearing UM-PEL-1 xenografts after treatment for 24 hours with PBS or bortezomib. Both arms of the experiment had three mice and the RNA was pooled from the three treated mice for gene expression analysis.
2010-07-20 | E-GEOD-22594 | biostudies-arrayexpress
Project description:Primary effusion lymphoma is an aggressive B-cell lymphoma most commonly diagnosed in HIV-positive patients and universally associated with Kaposi’s sarcoma-associated herpesvirus (KSHV). Chemotherapy treatment of PEL yields only short-term remissions in the vast majority of patients yet efforts to develop superior therapeutic approaches have been impeded by lack of animal models that more accurately mimic human disease. To address this issue we developed a direct xenograft model, UM-PEL-1, by transferring freshly-isolated human PEL cells into the peritoneal cavities of NOD/SCID mice without in vitro cell growth. We utilized this model to show that bortezomib induces PEL remission and extends overall survival of mice bearing lymphomatous effusions. Transcriptome analysis by genomic arrays revealed that bortezomib downregulated cell cycle progression, DNA replication, and Myc-target genes.
2010-07-20 | GSE22594 | GEO
Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples from patients with bortezomib responsive versus bortezomib resistant myeloma after 6-8 hours incubation in vitro with bortezomib 2 µg/ml or with PBS. Case D also had a fresh BM sample taken 75 minutes after IV injection of bortezomib.
2013-11-01 | GSE51940 | GEO
Project description:Transcriptional profiling of N-Tera2 differentiated human neuronal cells, comparing control uninfected cells to HCoV-OC43 infected cells at 24, 48 and 72 hour post-infection Keywords: Cell response to viral infection Two-condition experiment, N-Tera2 differentiated human neuronal cell mock infected vs. N-Tera2 differentiated human neuronal cell HCoV-OC43 infected at 24, 48 and 72 hours. Biological replicates: 2 at each time-course point. Technical replicate: 2 dye-swap at each time-point. 2 arrays hybridized with mock(cy3) vs infected(cy5) and 2 array with infected(cy3) vs mock(cy5).
2008-12-10 | E-GEOD-13879 | biostudies-arrayexpress
Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and directchum regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Genome-wide examination of histone H3 and H4 acetylation, as well as ACSS2 binding, in undifferentiated CAD cells and differentiated CAD neurons; background adjusted by H3 ChIP or Input.
2017-05-01 | E-GEOD-76850 | biostudies-arrayexpress
Project description:Bortezomib induces anti-multiple myeloma immune response mediated by cGAS/STING pathway activation
| PRJNA721176 | ENA
Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).
2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress
Project description:MicroRNA microarray profilling analysis was performed on exosomes derived from serum in patients with myeloma in two conditions of therapeutic efficacy, Bortezomib resistance and Bortezomib response. Bortezomib is approved and widely used treating myeloma.
2016-07-31 | GSE71435 | GEO