Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors.
3D-genome
ATAC-seq
Down syndrome
Hi-C
RNA-seq
aneuploidy
epigenome
lamina-associated domains (LADs)
senescence
senolytic drugs
transcriptome
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
06 01 2022
06 01 2022
Historique:
received:
10
05
2020
revised:
30
08
2021
accepted:
09
12
2021
entrez:
7
1
2022
pubmed:
8
1
2022
medline:
28
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34995493
pii: S1934-5909(21)00486-0
doi: 10.1016/j.stem.2021.12.002
pmc: PMC8805993
mid: NIHMS1769877
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
116-130.e7Subventions
Organisme : NHGRI NIH HHS
ID : U54 HG008097
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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