Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
Project description:In order to understand the role of heterodimeric hypoxia-inducible factors (HIF) in non-alcoholic fatty liver disease, we subjected wild type and Hif1-alpha mutant mice to nutritional stress conditions imposed by switching from fasting to re-feeding. Liver samples and subsequently RNA were extracted at each time point and used to comprehensively characterise transcriptional changes using microarray technology. We provide biological replicates for each of the conditions.
Project description:This agent-based model is based on an adaptive laboratory evolution (ALE) experiment scenario of two mutually cross feeding strains of bacteria and yeast. The bacterial strain secretes vitamins for which the yeast strain is auxotrophic and the yeast strain secrets amino acids for which the bacterial strain is auxotrophic. In particular, the model simulates a situation where a mutation arises in the bacterial strain that results in the emergence of individuals (mutant bacteria) with a higher secretion of vitamins as compared to the wild type (WT). This increase in secretion comes with a cost in terms of fitness (growth rate) of the mutant bacteria. The model can be used to assess if this mutant is able to persist and increase in frequency in the cross-feeding community.
Project description:To explore the possible changes of gene expression induced by a carcinogen, we treated wild-type and Dicer1-KO mice with one dose of 120 mg/kg N-ethyl-N-nitrosourea (ENU), a model genotoxic carcinogen, and vehicle control. The gene expression profiles were assessed in the mouse livers in wild-type and Dicer1-KO mice design. Total RNA were isolated from the livers at days 15 after the treatment and their expression was determined using Gene Array.
Project description:We performed the transcripome-wild m6A-sequencing to compare the m6A profiles of negative control (NC) HeLa cells and ALKBH5 KO HeLa cells stably re-expressing wild type ALKBH5 (WT) or its mutant K235R (K235R)
Project description:Expression data from livers of female wild-type mice subjected to warm bilateral renal artery ischemia-reperfusion injury (RIR) in comparison to livers of female wild type mice subjected to sham surgery.
Project description:Expression data from livers of male wild-type mice subjected to warm bilateral renal artery ischemia-reperfusion injury (RIR) in comparison to livers of male wild type mice subjected to sham surgery.
Project description:Profiling of H3K79me2 occupancy in wild-type N2 day-1 adult worms subjected to L1 larval starvation (STV) or ad libitum feeding (Fed).
Project description:Insulin action initiates a series of phosphorylation events regulating cellular differentiation, growth and metabolism. We have previously discovered, in a mass spectrometry-based phosphoproteomic study, that insulin/IGF-1 signaling induces phosphorylation of retinoid x receptor alpha (RXRα) at S22 in mouse brown pre-adipocytes. Here, we show that insulin induces the phosphorylation of RXRα at S22 in both brown precursor and mature adipocytes through a pathway involving ERK, downstream of IRS-1 and -2. We also found that RXRα S22 phosphorylation is promoted by insulin and upon re-feeding in brown adipose tissue in vivo, and that insulin-stimulated S22 phosphorylation of RXRα is dampened by diet-induced obesity. We used Rxra knockout cells re-expressing wild type (WT) or S22A non-phosphorylatable forms of RXRα to further characterize the role of S22 in brown adipocytes. Knockout of Rxra in brown pre-adipocytes resulted in decreased lipid accumulation and adipogenic gene expression during differentiation, and re-expression of RxraWT alleviated these effects. However, we observed no significant difference in cells re-expressing the RxraS22A mutant as compared with the cells re-expressing RxraWT. Furthermore, comparison of gene expression during adipogenesis in the WT and S22A re-expressing cells by RNA sequencing revealed similar transcriptomic profiles. Thus, our data propose a dispensable role for RXRα S22 phosphorylation in adipogenesis and transcription in differentiating brown pre-adipocytes.