Cited by 104Down syndrome and intellectual disability researchTelomeres, Telomerase, and SenescenceGenomics and Chromatin Dynamics

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

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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·2022·Cell Stem Cell

DOI 10.1016/j.stem.2021.12.002PMC PMC8805993

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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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Prevalence and diversity of retinal disease in adults with Down syndrome
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Biallelic null variants in PNPLA8 cause microcephaly through the reduced abundance of basal radial gliaPreprint
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Chromosome engineering to correct a complex rearrangement on Chromosome 8 reveals the effects of 8p syndrome on gene expression and neural differentiationPreprint
Lee, S. N., Banda, E. C., Qiao, L., Thompson, S. L., Singh, K., Hagenson, R. A., Davoli, T., Pinter, S. F., & Sheltzer, J. M. (2026) · Genome Research · doi:10.1101/gr.280425.125 · Cited by 1
Additional file 7 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186068
Additional file 5 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186062
Additional file 6 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186065
Additional file 3 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186056
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Jandy, M., Hu, H., Liu, Y., & Bhattacharyya, A. (2025) · Springer eBooks · doi:10.1007/978-3-031-78611-2_7
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Close parallels between cannabis use and deteriorating US Mental Health at four levels supports and extends the epidemiological salience of demonstrated causal mental health relationships: A geospatiotemporal study
Reece, A. S., & Hulse, G. K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-13492-0.00002-5
Additional file 9 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186074
Additional file 2 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.24779417
Additional file 9 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651580
Additional file 6 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651571
Additional file 1 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186050
Additional file 5 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651568
Additional file 2 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186053
Additional file 4 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651565
Additional file 3 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & 廖世秀 (2024) · Figshare · doi:10.6084/m9.figshare.26651562
Additional file 7 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651574
Additional file 1 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2023) · Figshare · doi:10.6084/m9.figshare.24779223
Additional file 4 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186059
Additional file 8 of Transcriptomic analysis of stem cells from chorionic villi uncovers the impact of chromosomes 2, 6 and 22 in the clinical manifestations of Down syndrome
Vaiasicca, S., Melone, G., James, D. W., Quintela, M., Preziuso, A., Finnell, R. H., Conlan, R. S., Francis, L. W., & Corradetti, B. (2023) · Figshare · doi:10.6084/m9.figshare.24186071
Additional file 8 of Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome
Guo, Z., Zhu, Y., Xiao, H., Dai, R., Yang, W., Xue, W., Zhang, X., Hao, B., & Liao, S. (2024) · Figshare · doi:10.6084/m9.figshare.26651577
Neuronal and microglial fine-tuned 3D DNA foundation models dissect genetic variants in Alzheimer’s diseasePreprint
Cheng, F., Ren, Y., Paz, M., Yang, X. J., Li, Y., Hou, Y., Li, Y., Jin, F., Hu, M., & Pieper, A. A. (2026) · Research Square · doi:10.21203/rs.3.rs-8920766/v1
Anti-inflammatory and pro-proliferative effects of fasudil in human trisomy 21 neural progenitor cellsPreprint
Baxter, L. L., Lee, S. E., Fuentes, K. A., Mosley, I. A., Raymond, J. D., Guedj, F., Zhou, D., Slonim, D. K., Glotfelty, E. J., Tweedie, D., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.19.712922
Molecular Pathogenesis of Down Syndrome (Trisomy 21)
Tlekhatuk, Z. I., Sutiagina, V. M., Linchevsky, A. A., Pushnova, A. S., Polyakov, P. P., Zanin, S. A., Владимирович, Ц. О., Naumenko, D. A., & Akhrorova, M. S. (2026) · Innovative medicine of Kuban · doi:10.35401/2541-9897-2026-11-2-140-146

Authors: Meharena, H. S., Marco, A., Dileep, V., Lockshin, E. R., Akatsu, G. Y., Mullahoo, J., Watson, L. A., Ko, T., Guerin, L. N., Abdurrob, F., Rengarajan, S., Papanastasiou, M., Jaffe, J. D., & Tsai, L.-H.
Affiliations: Massachusetts Institute of Technology (US)
Broad Institute (US)
Corresponding author: Meharena, Hiruy S.
Tsai, Li-Huei
ORCID: Meharena, Hiruy S.
Marco, Asaf
Dileep, Vishnu
Lockshin, Elana R.
Akatsu, Grace Y.
Mullahoo, James
Guerin, Lindsey N.
Abdurrob, Fatema
Rengarajan, Shruthi
Papanastasiou, Malvina
Jaffe, Jacob D.
Tsai, Li-Huei
Venue: Cell Stem Cell
Publisher: Elsevier BV
Published: 2022-01
Volume: 29
Issue: 1
Pages: 116-130.e7
ISSN: 1875-9777 (ISSN-L)
1934-5909
DOI: 10.1016/j.stem.2021.12.002
PMC: PMC8805993
OpenAlex: W4205519160
Cited by: 92
References: 137
Citations by year: 2026: 14 · 2025: 19 · 2024: 19 · 2023: 29 · 2022: 11
FWCI: 19.84
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cell stem cell (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
Funders: National Institutes of Health (3U54HG008097-05S1)
Burroughs Wellcome Fund
Massachusetts Institute of Technology
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: Down syndrome, cellular senescence, neural progenitor cells, nuclear organization, lamina-associated domains, chromatin accessibility, senolytics, iPSC-derived neural progenitor cells
MeSH terms: Down Syndrome, Humans, Gene Expression Profiling, Induced Pluripotent Stem Cells, Neural Stem Cells, Transcriptome

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

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