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:Polyploidy has been implicated in genome instability and tumorigenesis. We use Schizosaccharomyces pombe diploids as a model for studying the consequences of whole genome duplications on genome integrity. In this study, our aim is to investigate the transcriptional profile between haploid and diploid S. pombe in unperturbed and MMS treated conditions (0.0075% MMS, 4 hours @ 32 degrees Celsius in YES media).
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:Major depressive disorder (MDD) and bipolar disorder (BD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two diseases in clinical symptoms, treatment strategies, and genetic etiology. Here we use a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls) of Han Chinese origin to investigate their shared genetic basis, followed by exploration of the underlying mechanisms. The lead SNP in the Han Chinese meta-analysis, rs126277 at the 1q32.2 locus, also exhibited nominal associations with mood disorders as well as several sub-clinical phenotypes (e.g., mania) related to mood disorders (UK biobank samples) in European populations. Bulk tissue and single-cell eQTL studies suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brain tissues and cells, indicating possible involvement of this gene in mood disorders. We generated mice lacking Syt14 (Syt14–/–) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD). We found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in the mice. RNA-sequencing analyses of the hippocampus of Syt14–/– mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14–/– mice compared with control mice. And Syt14–/– mice exhibit aberrant glutamate signaling patterns in the hippocampus. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors and essential roles in synaptic function. While the current study provides clues for the pathological mechanisms of mood disorders, further investigations elucidating the detailed mechanisms by which SYT14 regulates mood disorders-related traits are needed.
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: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
