TS-EUROTRAIN - Projects

Epigenetic and functional characterization of proposed genetic variants and regions implicated in the pathogenesis of TS and related phenotypes (WP1)

Objectives: 1. Functional characterization of genetic polymorphisms in miR regulated expression of candidate genes in TS. 2. Identify epigenetic regulatory markers in cell lines and model animals treated with dopaminergic and glutamatergic modulating compounds. 3. Characterize whole genome methylation changes possibly involved in the pathogenesis of TS and co-morbid disorders.

Fellow ESR4   
Host institution: Semmelweis University
Duration: 36 months    
Supervisor: C. Barta, Semmelweis; Co-supervisor: Z. Tümer, KC; Associated partner: T. Aranyi, IOE; Seconding Company: deCODE.

Tasks and methodology: Candidate non-coding RNAs, mainly microRNAs (miRs), which are involved in the control of tissue-specific gene expression will be studied by in vivo target validation of in silico proposed miR target genes and functional characterization of genetic polymorphisms in miR regulated expression of candidate genes in TS. Expression analyses will be performed on neuronal cell lines, such as human neuroblastoma IMR32, SH-SY5Y and SK-NF1 and retinoblastoma Y79 lines. MiR assays will be performed at Semmelweis and KC. Epigenetic changes upon treatments of cell lines with dopaminergic and glutamatergic modulating compounds (aripiprazole and riluzole, both used in WP3) will also be investigated at IOE. Whole genome DNA methylation will be assessed using promoter or CpG island specific microarrays or MeDIP sequencing. Target genetic regions will be analyzed by bisulfite genomic sequencing (BSG). Cells will be studied by chromatin immunoprecipitation (ChIP) to determine histone acetylation profiles. Brain tissue samples from animal models developed in WP3 will be studied for epigenetic changes. Specific regions of the CNS implicated in these newly developed neurodevelopmental animal models will be investigated by MeDIP-seq to determine DNA methylation profiles. Through a secondment at deCODE, the student will receive further training in analyzing genomewide methylation profiles. Epigenetic effects of treatment with dopaminergic and glutamatergic compounds will also be assessed.

  • Task 1: Characterization of implicated genetic regions for miR regulated gene expression using miR assays and expression profiling.
  • Task 2: Epigenetic profiling in target gene regions in treated and untreated neuronal cell cultures.
  • Task 3: Screening of whole genome DNA methylation changes in brain samples from treated and untreated animal models used in collaborating groups by different techniques (promoter or CpG island specific microarrays or MeDIP sequencing) or at target genetic regions by BSG.

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