Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells

John N. Mariani; Benjamin Mansky; Pernille M. Madsen; Dennis Salinas; Deniz Kesmen; Nguyen P.T. Huynh; Nicholas J. Kuypers; Erin R. Kesel; Janna Bates; Casey Payne; Devin Chandler-Militello; Abdellatif Benraiss; Steven A. Goldman

doi:10.1038/s41467-024-48118-2

Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells

John N. Mariani^*, Benjamin Mansky, Pernille M. Madsen, Dennis Salinas, Deniz Kesmen, Nguyen P.T. Huynh, Nicholas J. Kuypers, Erin R. Kesel, Janna Bates, Casey Payne, Devin Chandler-Militello, Abdellatif Benraiss, Steven A. Goldman

^*Corresponding author af dette arbejde

Center for Translational Neuromedicine

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

4 Citationer (Scopus)

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Abstract

Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.

Originalsprog	Engelsk
Artikelnummer	3873
Tidsskrift	Nature Communications
Vol/bind	15
Udgave nummer	1
Antal sider	19
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-024-48118-2
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by the Adelson Medical Research Foundation, and NIH grants R01NS110776 and R01AG072298 to S.G, as well as by CNS2, Inc., and by a Novo Nordisk Foundation grant to P.M. We thank Roman Lu\u0161trik (Genialis) for assistance in deploying the Shiny app, and Lorenz Studer (Memorial Sloan-Kettering) for his generous provision of the C27 hiPS cells.

Publisher Copyright:
© The Author(s) 2024.

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10.1038/s41467-024-48118-2Licens: CC BY

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Citationsformater

Mariani, J. N., Mansky, B., Madsen, P. M., Salinas, D., Kesmen, D., Huynh, N. P. T., Kuypers, N. J., Kesel, E. R., Bates, J., Payne, C., Chandler-Militello, D., Benraiss, A., & Goldman, S. A. (2024). Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells. Nature Communications, 15(1), Artikel 3873. https://doi.org/10.1038/s41467-024-48118-2

Mariani, JN, Mansky, B, Madsen, PM, Salinas, D, Kesmen, D, Huynh, NPT, Kuypers, NJ, Kesel, ER, Bates, J, Payne, C, Chandler-Militello, D, Benraiss, A & Goldman, SA 2024, 'Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells', Nature Communications, bind 15, nr. 1, 3873. https://doi.org/10.1038/s41467-024-48118-2

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title = "Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells",

abstract = "Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.",

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AU - Mariani, John N.

AU - Mansky, Benjamin

AU - Madsen, Pernille M.

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AU - Kesmen, Deniz

AU - Huynh, Nguyen P.T.

AU - Kuypers, Nicholas J.

AU - Kesel, Erin R.

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AU - Payne, Casey

AU - Chandler-Militello, Devin

AU - Benraiss, Abdellatif

AU - Goldman, Steven A.

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N2 - Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.

AB - Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.

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