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Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons - RNA-Seq data on transcriptional changes induced by 1µM paclitaxel treatment for 24h

ABSTRACT: We report data on transcriptome sequencing analyses of functional iPSC-DSN (maturation >d40) treated with 1 µM paclitaxel for 24h compared to DMSO treatment. RNA-Sequencing analyses revealed 319 significantly differentially (padjusted <0.01) expressed genes out of which 227 were upregulated and 92 downregulated. 84 of the upregulated and 33 of the downregulated changed expression by at least 2 fold. Upregulated genes involve known neuronal injury markers such as the Activation Transcription Factor (ATF3), stress-inducible proteins such as Sestrin-2 (SESN2), apoptosis associated genes such as Caspase 3 (CASP3), the JUN proto-oncogene (JUN) or BCL2-interacting proteins such as BBC3 or Harakiri (HRK). Also, vasoactive substances and pain inducing neuropeptides of the calcitonine gene related peptide family such as CALCB and adrenomedullin (ADM) were found amongst the top 50 differentially regulated genes. Downregulated genes involve pathways of sterol homeostasis, glucose homeostasis and lipogenesis, e.g., 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 (HMGCS1), Insulin Induced Gene 1 (INSIG1) or ELOVL Fatty Acid Elongase 6 (ELOVL6). Gene set enrichment analysis outlined significant deregulation of genes involved in cholesterol biosynthesis pathways, PERK regulated genes and genes involved in amino acid transport across the membrane. In summary, there is a significant overlap of the above mentioned genes and gene sets outlined by unbiased global differential transcriptome analyses with pathways known from the literature of neuropathy and neurodegeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173610 | GEO | 2021/04/30

REPOSITORIES: GEO

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Project description:Reversible protein phosphorylation is one of the most important posttranslational modifications (PTMs) due to its vital role in cellular functions and signaling pathways. Protein phosphorylation is also known to be involved in the regulation of apoptosis. Previously, we have performed a SILAC-based analysis of phosphotyrosinylation of cisplatin-induced apoptotic Jurkat T cells. To further expand this study, we used the same experimental setup and analyzed the global phosphorylation profile. The different steps of the phosphopeptide enrichment protocol using TiO2 beads were tested and the best approach was applied in combination with LC-MS with different normalized collision energy (NCE) values for HCD fragmentation. In total, more than 2,000 phosphoproteins of more than 4,000 phosphopeptides were identified in the four biological replicates of both states. HCD with NCE 25 accounted for 64% and NCE 35 for 36 % of identified phosphopeptides. 425 phosphopeptides were found to be significantly regulated in cisplatin-treated against control samples. KEGG pathway analysis revealed splicosomal proteins and the MAPK signaling pathway to be upregulated and cell cycle proteins to be downregulated. The transcription factors Atf2 and Jun, which are both involved in the MAPK signaling pathway, were further investigated. For Jun, more than 90 spectral counts were found only in apoptotic cells and covered the well-known stress induced phosphorylation sites at S-63/S-73, as well as S-243 which reduces the ability to bind DNA and is required for GSK3 mediated ubiquitinylation at S-239. For Atf2, more than 60 spectral counts were found in apoptotic cells vs. 8 in control cells. Most significantly upregulated sites for Atf2 have been identified at S-90 and S-112, which are less well studied phosphorylation sites of Atf2 as several other sites. Western blot analyses using non-phosphorylated and phosphorylated antibodies were performed to validate the phosphorylation events of Jun and Atf2. Our findings contribute to the current knowledge of the phosphorylation profiles of apoptotic cells.

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Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons - RNA-Seq data on transcriptional changes induced by 1µM paclitaxel treatment for 24h

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