First name
Alessandro
Last name
Vitriolo
Year of Study
Research Center
Thesis Title
Multi-omic deconvolution of the regulatory networks underlying neurodevelopmental and autism spectrum disorders: a multidimensional analysis for a new disease modelling paradigm
Thesis Abstract
Multi-omic deconvolution of the regulatory networks underlying neurodevelopmental and autism spectrum disorders: a multidimensional analysis for a new disease modelling paradigm
Recent literature has highlighted that mutations causing neurodevelopmental syndromes are particularly enriched in genes related to chromatin. Most of such disorders couple different shades of intellectual disabilities with peculiar cranio- facial features and systemic defects which turned out to be shared, opposite or unique across them. Building on our expertise to harness potency and stability of induced pluripotent stem cells (iPSCs), we identified two main axes of development through which we characterized on the one hand cerebral cortex related dysregulations and on the other hand cranio-facial features associated traits, peripheral nervous system- and cardiovascular system-related dysregulations. First, we identified transcriptional modules and disease-specific dysregulations reverberating from the pluripotent stage to disease-relevant tissues. Then, we identified a set of putative direct targets of PRC2 complex involved in early brain development and BAZ1B-specific transcriptional dysregulations in neural crest stem cells, that confirm its importance for migration and craniofacial morphogenesis but more in general for chromatin remodelling and modern human evolution. Finally, we produced a molecular characterization of KMT2D function in adult cortical neurons. In doing so we developed new tools and standards for NGS-based differential expression analyses, and an analytical framework to boost the ability of identifying the effect of knocking down a certain gene on transcriptional and epigenetic landscapes.
Recent literature has highlighted that mutations causing neurodevelopmental syndromes are particularly enriched in genes related to chromatin. Most of such disorders couple different shades of intellectual disabilities with peculiar cranio- facial features and systemic defects which turned out to be shared, opposite or unique across them. Building on our expertise to harness potency and stability of induced pluripotent stem cells (iPSCs), we identified two main axes of development through which we characterized on the one hand cerebral cortex related dysregulations and on the other hand cranio-facial features associated traits, peripheral nervous system- and cardiovascular system-related dysregulations. First, we identified transcriptional modules and disease-specific dysregulations reverberating from the pluripotent stage to disease-relevant tissues. Then, we identified a set of putative direct targets of PRC2 complex involved in early brain development and BAZ1B-specific transcriptional dysregulations in neural crest stem cells, that confirm its importance for migration and craniofacial morphogenesis but more in general for chromatin remodelling and modern human evolution. Finally, we produced a molecular characterization of KMT2D function in adult cortical neurons. In doing so we developed new tools and standards for NGS-based differential expression analyses, and an analytical framework to boost the ability of identifying the effect of knocking down a certain gene on transcriptional and epigenetic landscapes.
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