Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors
Name
1-s2.0-S1934590921004860-main.pdf
Description
Published version
Size
5.84 MB
Format
Adobe PDF
Checksum (MD5)
11f9fea25b3d95be5082d13a630f4847
Author(s)
Meharena, Hiruy S
Marco, Asaf
Dileep, Vishnu
Lockshin, Elana R
Akatsu, Grace Y
Mullahoo, James
Watson, L Ashley
Ko, Tak
Guerin, Lindsey N
Abdurrob, Fatema
Date Issued
2022
Journal
Cell Stem Cell
Publisher
Elsevier BV
Citation
Meharena, Hiruy S, Marco, Asaf, Dileep, Vishnu, Lockshin, Elana R, Akatsu, Grace Y et al. 2022. "Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors." Cell Stem Cell, 29 (1).
Version
Final published version
Abstract
Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) and characterized by a wide range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide "chromosomal introversion," disruption of lamina-associated domains, and global chromatin accessibility changes in response to T21, consistent with the transcriptional and nuclear architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular, and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.STEM.2021.12.002
