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Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors.
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; Rengarajan, Shruthi; Papanastasiou, Malvina; Jaffe, Jacob D; Tsai, Li-Huei.
Afiliação
  • Meharena HS; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: hiruym@mit.edu.
  • Marco A; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Dileep V; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Lockshin ER; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Akatsu GY; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Mullahoo J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Watson LA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Ko T; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Guerin LN; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Abdurrob F; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Rengarajan S; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Papanastasiou M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Jaffe JD; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Tsai LH; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: l
Cell Stem Cell ; 29(1): 116-130.e7, 2022 01 06.
Article em En | MEDLINE | ID: mdl-34995493
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome de Down / Células-Tronco Pluripotentes Induzidas / Células-Tronco Neurais Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome de Down / Células-Tronco Pluripotentes Induzidas / Células-Tronco Neurais Idioma: En Ano de publicação: 2022 Tipo de documento: Article