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

Research output: Contribution to journalArticlepeer-review

46 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 languageEnglish
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.

Funding

This work was supported by grants from the Alana foundation (received byL.-H.T.), the LuMind Foundation (received by H.S.M.), Burroughs Wellcome Fund (received by H.S.M.), UNCF-Merck postdoctoral fellowship (received by H.S.M.), and the National Institute of Health (3U54HG008097-05S1, received by J.D.J. and L.-H.T.). We would like to thank Dr. Jay Penney, Dr. Scarlett Barker, Dr. Matheus Victor, Dr. Ravikiran Raju, Dr. Priyanka Narayan, Dr. Ping-Chieh Pao, Dr. Emily Niederst, and the members of Tsai Lab for all the constructive discussions and feedback on the manuscript. We would also like to thank Ying Zhou and Dr. Jennie Young of the Tsai Lab, as well as Dr. Stuart Levine and his entire team at the MIT BioMicro Center. We would also like to thank Dr. Stuart Orkin for sharing the isogenic pair iPSCs utilized in this manuscript. We would also like to acknowledge that cartoon illustrations were created withBioRender.com. H.S.M. and L.-H.T. conceptualized and designed the project. H.S.M. and T.K. generated iPSCs and NPCs. H.S.M. E.R.L. G.Y.A. and L.N.G. performed cell culture experiments. H.S.M. L.A.W. E.R.L. G.Y.A. L.N.G. and F.A. performed immunostaining, imaging, and IMARIS analysis. H.S.M. E.R.L. G.Y.A. and S.R. performed RNA-seq experiments. H.S.M. A.M. E.R.L. and S.R. performed ATAC-seq library preparation. H.S.M. and S.R. performed Hi-C library preparation, and H.S.M. performed ChIP-seq library preparation and data analysis. H.S.M. A.M. and V.D. performed computational analysis. J.M. and M.P. performed global chromatin profiling experiments, and J.M. and H.S.M. performed data analysis. H.S.M. L.A.W. A.M. V.D. E.R.L. G.Y.A. J.M. M.P. and L.-H.T. wrote the manuscript with the input from all authors. L.-H.T. and J.D.J. provided the resources for the project. The authors declare no competing interests. This work was supported by grants from the Alana foundation (received byL.-H.T.), the LuMind Foundation (received by H.S.M.), Burroughs Wellcome Fund (received by H.S.M.), UNCF-Merck postdoctoral fellowship (received by H.S.M.), and the National Institute of Health (3U54HG008097-05S1, received by J.D.J. and L.-H.T.). We would like to thank Dr. Jay Penney, Dr. Scarlett Barker, Dr. Matheus Victor, Dr. Ravikiran Raju, Dr. Priyanka Narayan, Dr. Ping-Chieh Pao, Dr. Emily Niederst, and the members of Tsai Lab for all the constructive discussions and feedback on the manuscript. We would also like to thank Ying Zhou and Dr. Jennie Young of the Tsai Lab, as well as Dr. Stuart Levine and his entire team at the MIT BioMicro Center. We would also like to thank Dr. Stuart Orkin for sharing the isogenic pair iPSCs utilized in this manuscript. We would also like to acknowledge that cartoon illustrations were created with BioRender.com .

FundersFunder number
Alana foundation
LuMind Foundation
MIT BioMicro Center
NPCs
UNCF-Merck
National Institutes of Health
National Human Genome Research InstituteU54HG008097
Burroughs Wellcome Fund

    Keywords

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

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