First name
Giuseppe
Last name
D'Agostino
Year of Study
Research Center
Thesis Title
Propagation of dysregulation across gene expression layers in 7q11.23 CNVassociated developmental disorders
Thesis Abstract
Williams-Beuren Syndrome (WBS) and 7q11.23 microduplication syndrome (7dup), two multisystemic
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.
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.
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