Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability
Authors
Mihajlović, MarijaGermain, Pierre-Luc
Shyti, Reinald
Pozzi, Davide
Noberini, Roberta
Liu, Yansheng
Aprile, Davide
Troglio, Flavia
Bonaldi, Tiziana
Aebersold, Rudolf
Matteoli, Michela
Testa, Giuseppe
Contributors
Morić, IvanaĐorđević, Valentina
Conference object (Published version)
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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 7...Dup. 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.
Source:
5th Belgrade Bioinformatics Conference, 2024, 38-Publisher:
- Belgrade : Institute of Molecular Genetics and Genetic Engineering
Note:
- Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024.
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - CONF AU - Mihajlović, Marija AU - Germain, Pierre-Luc AU - Shyti, Reinald AU - Pozzi, Davide AU - Noberini, Roberta AU - Liu, Yansheng AU - Aprile, Davide AU - Troglio, Flavia AU - Bonaldi, Tiziana AU - Aebersold, Rudolf AU - Matteoli, Michela AU - Testa, Giuseppe PY - 2024 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2453 AB - 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. PB - Belgrade : Institute of Molecular Genetics and Genetic Engineering C3 - 5th Belgrade Bioinformatics Conference T1 - Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability SP - 38 SP - 38 UR - https://hdl.handle.net/21.15107/rcub_imagine_2453 ER -
@conference{ author = "Mihajlović, Marija and Germain, Pierre-Luc and Shyti, Reinald and Pozzi, Davide and Noberini, Roberta and Liu, Yansheng and Aprile, Davide and Troglio, Flavia and Bonaldi, Tiziana and Aebersold, Rudolf and Matteoli, Michela and Testa, Giuseppe", year = "2024", 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.", publisher = "Belgrade : Institute of Molecular Genetics and Genetic Engineering", journal = "5th Belgrade Bioinformatics Conference", title = "Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability", pages = "38-38", url = "https://hdl.handle.net/21.15107/rcub_imagine_2453" }
Mihajlović, M., Germain, P., Shyti, R., Pozzi, D., Noberini, R., Liu, Y., Aprile, D., Troglio, F., Bonaldi, T., Aebersold, R., Matteoli, M.,& Testa, G.. (2024). Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability. in 5th Belgrade Bioinformatics Conference Belgrade : Institute of Molecular Genetics and Genetic Engineering., 38. https://hdl.handle.net/21.15107/rcub_imagine_2453
Mihajlović M, Germain P, Shyti R, Pozzi D, Noberini R, Liu Y, Aprile D, Troglio F, Bonaldi T, Aebersold R, Matteoli M, Testa G. Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability. in 5th Belgrade Bioinformatics Conference. 2024;:38. https://hdl.handle.net/21.15107/rcub_imagine_2453 .
Mihajlović, Marija, Germain, Pierre-Luc, Shyti, Reinald, Pozzi, Davide, Noberini, Roberta, Liu, Yansheng, Aprile, Davide, Troglio, Flavia, Bonaldi, Tiziana, Aebersold, Rudolf, Matteoli, Michela, Testa, Giuseppe, "Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, mTOR and neuronal maturation and excitability" in 5th Belgrade Bioinformatics Conference (2024):38, https://hdl.handle.net/21.15107/rcub_imagine_2453 .