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Mechanism of DNA methyltransferase DNMT3L in regulating synaptic protein expression during abnormal cortical development in Down syndrome
China (IFMSA-China) - China Medical University, Shenyang
Department of Human Anatomy
Type of Research Project
- Basic science
What is the background of the project?
Intellectual disability is the most profound neurological features of Down syndrome and studies on synaptic plasticity are essential to understand its pathological mechanisms. We recently observed global hypermethylation in the fetal brain of Down syndrome compared to that of normal people, and over-expression of chromosome 21 gene DNMT3L (DNA methyltransferase 3-like) changed the expressions of some synaptic proteins ，such as PSD95(postsynaptic density protein 95)， APP（Amyloid precursor protein）. Thus, we hypothesize that over-expression of DNMT3L causes global hypermethylation through stimulating DNMT3A（DNA methyltransferase 3A） and DNMT3B（DNA methyltransferase 3B）, or reduced methylation of histones related to active gene transcription through inhibiting histone methyltransferases; both may alter the downstream gene expression ( Tumor protein p53，TP53;discs, large homolog 4,DLG4;APP) and cause some Down syndrome phenotypes including lowered synaptic plasticity and learning and memory deficits.
What is the aim of the project?
We aim to build neural cell and animal models with three-copy DNMT3L, examine the genomic DNA methylation and gene expression, search for DNMT3L targeting genes, explore the molecular mechanisms of DNMT3L over-expression causing hypermethylation of targeting genes and altered gene expression, and observe its effects on abnormal neural development to prove the above hypothesis and provide theoretical and experimental basis for the early diagnosis and therapy of this disorder.
What techniques and methods are used?
We will make a three-copy DNMT3L neuronal cell model by using gene targeting technique to detect genomic methylation and gene expression by using methylation chip and RNA sequencing technique, and search for possible target genes of DNMT3L. Chromosome immunoprecipitation technique will be used to search for direct target genes of DNMT3L, and to investigate the methylation and gene expression of downstream target genes induced by DNMT3L. The three-copy DNMT3L transgenic mouse model will be made by using chromosome recombination to observe the effect of DNMT3L overexpression on the neurodevelopmental phenotype.
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
After the training, the students need to show their basic knowledge and skills in literature searching, experiment design, know how to do neural stem cell culture, molecular cloning, immunohistochemistry, Western blotting, animal breeding, and statistical analysis of the data. These will be evaluated by supervisors in the lab. The students are also expected to give a presentation on their small project, and a talk on journal paper review. They are expected to attend the lab meetings and contribute their opinions too.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Some lectures and seminars will be available for them in the campus by prof Lv
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a poster - The student will prepare a presentation - The student will prepare a scientific report - The student will prepare an abstract - The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Diligent, honest, fluent in English speaking, basic knowledge in biology, chemistry and mathematics.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields
- Lu J; Sheen V. Genetic and Epigenetic Mechanisms in Down Syndrome Brain. 2013 March 6; 2013. In: Down Syndrome [Internet]. Rijeka; Croatia: InTech; [237-61].
- Lu J; McCarter M; Lian G; Esposito G; Capoccia E; Delli-Bovi LC; et al. Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression. Hum Mol Genet. 2016;25(9):1714-27. doi: 10.1093/hmg/ddw043. PubMed PMID: 26911678; PubMed Central PMCID: PMCPMC4986328.
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