Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors

Hiruy S. Meharena*, Asaf Marco, Vishnu Dileep, Elana R. Lockshin, Grace Y. Akatsu, James Mullahoo, L. Ashley Watson, Tak Ko, Lindsey N. Guerin, Fatema Abdurrob, Shruthi Rengarajan, Malvina Papanastasiou, Jacob D. Jaffe, Li Huei Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageAmerican English
Pages (from-to)116-130.e7
JournalCell Stem Cell
Volume29
Issue number1
DOIs
StatePublished - 6 Jan 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • 3D-genome
  • aneuploidy
  • ATAC-seq
  • Down syndrome
  • epigenome
  • Hi-C
  • lamina-associated domains (LADs)
  • RNA-seq
  • senescence
  • senolytic drugs
  • transcriptome

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