PROPAGATION OF DYSREGULATION ACROSS GENE EXPRESSION LAYERS IN 7Q11.23 CNV ASSOCIATED DEVELOPMENTAL DISORDERS

Williams-Beuren Syndrome (WBS) and 7q11.23 microduplication syndrome (7dup), two multi-systemic developmental disorders, arise from symmetrical copy number variations of the same region on chromosome 7q. In WBS patients this region is deleted, whereas it is duplicated in 7dup individuals. These syndromes display a striking combination of shared and opposite clinical manifestations at the level of neuro-cognitive, craniofacial and cardiovascular features, thus pointing to a remarkable dosage-sensitive effect of a small group of genes on the development and maintenance of complex traits such as sociality, language and facial morphology. We derived a large cohort of induced pluripotent stem cells (iPSCs) from samples with WBS, 7dup and from healthy controls, and we demonstrated that, already at the pluripotent state, the transcriptome is dysregulated in pathways that map onto disease-related features. Moreover, these pathways were selectively dysregulated in differentiated lineages, thus demonstrating an anticipatory power of the pluripotent state. Building on these results, we expanded the view on the dysregulation in pluripotency by measuring three layers of gene expression: transcriptome, translatome and proteome. We mapped the propagation of differences across layers by integrating ribosome profiling and SWATH-MS proteomics, and we probed the extent to which a translation initiation factor included in the CNV, EIF4H, was responsible for the regulation of translation. We found that each layer of gene expression has its own differentially expressed genes, whose degrees of propagation can change between layers. Moreover, differentially expressed genes can cluster by different ways of propagation when they are compared to the levels of EIF4H