Project description:This study was designed to investigate the effect of a novel model of early life stress (MMS) on DNA methylation within the hypothalamus
Project description:Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors with small effect sizes are collectively associated with the pathophysiology of BD, the underlying molecular mechanisms, especially how environmental factors affect the brain genome, remain largely unknown. We revealed neuronal cell-type-specific, pathophysiology-related DNA methylation changes in the prefrontal cortex (PFC) of BD patients, highlighting the importance of the neural epigenome for understanding BD.
Project description:The cellular response to treatment with DNA-damaging substances at low concentrations which are genotoxic but do not have a strong cytotoxic effect are of special interest. In addition, environmental variations that influence growth conditions, e.g. different media, and individual fitness, e.g. different strains, are likely to influence and modulate the adverse effects of individual DNA damaging substances. At sub-cytotoxic levels, DNA damaging substances play an important role in the accumulation of genomic mutations. In longer living organisms, like humans and other mammals, exposure to DNA damaging substances over extended period of time is a critical factor that contributes to the development of various diseases and in particular of tumors. The aim of our work was to study how strain background and growth conditions influence respond to DNA damage caused by low doses of MMS and which part of these changes is responsible for their sensitivity to toxic conditions. We analyzed sensitivity of two yeast strains FF18984 and BY4742 to MMS in media with limited and full nutrient availability. Keywords: Yeast, S.cerevisiae, MMS, stress response, DNA damage
Project description:We are investigating the transcriptional response of Anc1 deficient yeast under basal and MMS exposed conditions; We used microarrays to detail the global programme of gene expression underlying the MMS response in WT and Anc1 deficient yeast Experiment Overall Design: Yeast strains either WT or Anc1 deficient were exposed or unexposed to MMS
Project description:This is transcription analysis of genes regulated by the INO80 chromatin remodeling complex in S-phase of the cell cycle after MMS treatment. Wildtype and ino80 mutant cells were first synchronized at G1 using alpha-factor, the cells were released in to S-phase in the presence of 0.02% MMS. After 45 minutes, total RNA was isolated and analyzed to identify genes that are regulated by INO80 under such conditions.
Project description:We are investigating the transcriptional response of Anc1 deficient yeast under basal and MMS exposed conditions We used microarrays to detail the global programme of gene expression underlying the MMS response in WT and Anc1 deficient yeast Keywords: dose
Project description:This is transcription analysis of genes regulated by the INO80 chromatin remodeling complex in S-phase of the cell cycle after MMS treatment.
Project description:Despite the high toxicity, alkylating agents are still at the forefront of several clinical protocols used to treat cancers. In this study, we investigated the mechanisms underlying alkylation damage responses, aiming to identify novel strategies to augment alkylating therapy efficacy. In this pursuit, we compared gene expression profiles of evolutionary distant cell types (D. melanogaster Kc167 cells, mouse embryonic fibroblasts and human cancer cells) in response to the alkylating agent methyl-methanesulfonate (MMS). We found that many responses to alkylation damage are conserved across species independent on their tumor/normal phenotypes. Key amongst these observations was the protective role of NRF2-induced GSH production primarily regulating GSH pools essential for MMS detoxification but also controlling activation of unfolded protein response (UPR) needed for mounting survival responses across species. An interesting finding emerged from a non-conserved mammalian-specific induction of mitogen activated protein kinase (MAPK)-dependent inflammatory responses following alkylation, which was not directly related to cell survival but stimulated the production of a pro-inflammatory, invasive and angiogenic secretome in cancer cells. Appropriate blocking of this inflammatory component blocked the invasive phenotype and angiogenesis in vitro and facilitated a controlled tumor killing by alkylation in vivo through inhibition of alkylation-induced angiogenic response, and induction of tumor healing.
