dc.contributor | Morić, Ivana | |
dc.contributor | Đorđević, Valentina | |
dc.creator | Mihajlović, Marija | |
dc.creator | Germain, Pierre-Luc | |
dc.creator | Shyti, Reinald | |
dc.creator | Pozzi, Davide | |
dc.creator | Noberini, Roberta | |
dc.creator | Liu, Yansheng | |
dc.creator | Aprile, Davide | |
dc.creator | Troglio, Flavia | |
dc.creator | Bonaldi, Tiziana | |
dc.creator | Aebersold, Rudolf | |
dc.creator | Matteoli, Michela | |
dc.creator | Testa, Giuseppe | |
dc.date.accessioned | 2024-07-24T21:56:14Z | |
dc.date.available | 2024-07-24T21:56:14Z | |
dc.date.issued | 2024 | |
dc.identifier.isbn | 978-86-82679-16-5 | |
dc.identifier.uri | https://imagine.imgge.bg.ac.rs/handle/123456789/2453 | |
dc.description.abstract | Copy number variation (CNV) at 7q11.23 causes Williams-Beuren (WBS) and 7q
microduplication syndrome (7Dup), neurodevelopmental disorders featuring intellectual
disability accompanied by symmetrically opposite neurocognitive features. Although
significant progress has been made in understanding the molecular mechanisms underlying
7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression
layers and their interplay remains elusive. Here, we uncovered 7q11.23 dosage-dependent
symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By
integrating transcriptomics, translatomics and proteomics of patient-derived and isogenic
induced neurons, we found that genes related to neuronal transmission follow 7q11.23
dosage and are transcriptionally controlled, while translational factors and ribosomal
genes are post-transcriptionally buffered. Consistently, we found phospho-RPS6 (pRPS6)
down-regulated in WBS and up-regulated in 7Dup. Surprisingly, phospho-4EBP (p4EBP)
was altered in the opposite direction reflecting dosage-specific changes in the total 4EBP
levels. This highlights both different dosage-sensitive deregulations of the mTOR pathway
as well as distinct roles of pRPS6 and p4EBP during neurogenesis. Our work demonstrates
the importance of multi-scale disease modeling across molecular and functional layers
and uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigm pair
of complex neurodevelopmental disorders and uncouples the roles of pRPS6 and p4EBPs
as mechanistically actionable relays in neurodevelopmental disorders. | sr |
dc.language.iso | en | sr |
dc.publisher | Belgrade : Institute of Molecular Genetics and Genetic Engineering | sr |
dc.rights | openAccess | sr |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | 5th Belgrade Bioinformatics Conference | sr |
dc.title | Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability | sr |
dc.type | conferenceObject | sr |
dc.rights.license | BY-NC-ND | sr |
dc.rights.holder | © 2024 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade | sr |
dc.citation.spage | 38 | |
dc.citation.spage | 38 | |
dc.description.other | Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024. | sr |
dc.identifier.fulltext | https://imagine.imgge.bg.ac.rs/bitstream/id/845701/BelBi2024-Book-of-Abstracts_1-16,38,141-142.pdf | |
dc.identifier.rcub | https://hdl.handle.net/21.15107/rcub_imagine_2453 | |
dc.type.version | publishedVersion | sr |