A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Bansal, Prakhar
• dc.contributor.author Banda, Erin C.
• dc.contributor.author Glatt-Deeley, Heather R.
• dc.contributor.author Stoddard, Christopher E.
• dc.contributor.author Linsley, Jeremy W.
• dc.contributor.author Arora, Neha
• dc.contributor.author Deleschaux, Cécile
• dc.contributor.author Ahern, Darcy T.
• dc.contributor.author Kondaveeti, Yuvabharath
• dc.contributor.author Massey, Rachael E.
• dc.contributor.author Nicouleau, Michael
• dc.contributor.author Wang, Shijie
• dc.contributor.author Sabariego Navarro, Miguel
• dc.contributor.author Dierssen, Mara
• dc.contributor.author Finkbeiner, Steven
• dc.contributor.author Pinter, Stefan F.
• dc.date.accessioned 2024-09-13T07:21:48Z
• dc.date.available 2024-09-13T07:21:48Z
• dc.date.issued 2024
• dc.description.abstract Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we derived trisomy 21 (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls from mosaic DS fibroblasts and equipped one chr21 copy with an inducible XIST transgene. Monoallelic chr21 silencing by XIST is near-complete and irreversible in iPSCs. Differential expression reveals that T21 neural lineages and iPSCs share suppressed translation and mitochondrial pathways and activate cellular stress responses. When XIST is induced before the neural progenitor stage, T21 dosage correction suppresses a pronounced skew toward astrogenesis in neural differentiation. Because our transgene remains inducible in postmitotic T21 neurons and astrocytes, we demonstrate that XIST efficiently represses genes even after terminal differentiation, which will empower exploration of cell type-specific T21 phenotypes that remain responsive to chr21 dosage.
• dc.description.sponsorship This work was supported by grants from the LuMind IDSC Foundation and the NIH (R35GM124926, with additional support from R01HL141324) to S.F.P. Support for work conducted at the Gladstone Institutes (to S.F.) came from R01 AG064579 with additional support from R01 LM013617, RF1 NS128800, and the JSRM Foundation. Work at the Centre for Genomic Regulation (to M.D.) was supported by the Fondation Jérôme Lejeune #2002, Fundació La Marató De TV 3 202212-30-31-32, and Agencia Estatal de Investigación (PID2019-110755RB-I00/AEI/10.13039/501100011033). We acknowledge support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya, and FPU fellowship (FPU19/04789) from Ministerio de Universidades (to M.S.-N.) The CIBER of Rare Diseases is an initiative of the ISCIII.
• dc.format.mimetype application/pdf
• dc.identifier.citation Bansal P, Banda EC, Glatt-Deeley HR, Stoddard CE, Linsley JW, Arora N, et al. A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction. Sci Adv. 2024 Jun 7;10(23):eadj0385. DOI: 10.1126/sciadv.adj0385
• dc.identifier.doi http://dx.doi.org/10.1126/sciadv.adj0385
• dc.identifier.issn 2375-2548
• dc.identifier.uri http://hdl.handle.net/10230/61083
• dc.language.iso eng
• dc.publisher American Association for the Advancement of Science (AAAS)
• dc.relation.ispartof Sci Adv. 2024 Jun 7;10(23):eadj0385
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110755RB-I00
• dc.rights Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.other Down, Síndrome de
• dc.subject.other Cromosoma humà 21
• dc.title A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion