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Research Aim

Our current research objective is to develop and implement our human chromosome engineering approaches aimed to identify and characterize putative causal epigenetic factors for neurodevelopmental diseases. Based on our previous work, our initial focus is placed on Autism Spectrum disorder (ASD) and Prader-Willi/Angelman syndrome, but we anticipate that our tool will be useful in the characterization of epigenetic factors for any other diseases such as Schizophrenia, Kabuki Syndrome.

Currently, we focus on a major subset of ASD associated to maternal 15q11-q13 duplications. We apply our microcell-mediated chromosome transfer (MMCT) of engineered segments of a maternal human chromosome 15 into human iPSC to develop a novel and versatile experimental system in which to pioneer the study of 15q11-q13 duplications in ASD.

The precise engineering of different types of 15q duplications commonly observed in ASD complements patient-derived ASD modeling by enabling the sequential dissection of the role of gene dosage in the same iPSC line and hence without the confounding effect of genetic background heterogeneity.

Upon differentiation into cortical neurons, these 15q-engineered iPSC will be subjected to neuoranatomical reconstruction. Finally, we will characterize the neuronal phenotype and behavior of mice engineered to harbor entire or partial human chromosomes 15, which were stably retained ensuring proper tissue-specific expression of human genes in adult mouse tissues. Therefore, these mouse models will permit to relate in vitro phenotypes of 15q engineered human neurons to whole animal ASD behavior.