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 and Steven A. Goldman ()
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John N. Mariani: University of Rochester Medical Center
Benjamin Mansky: University of Rochester Medical Center
Pernille M. Madsen: University of Rochester Medical Center
Dennis Salinas: University of Rochester Medical Center
Deniz Kesmen: University of Rochester Medical Center
Nguyen P. T. Huynh: University of Copenhagen Faculty of Health
Nicholas J. Kuypers: University of Rochester Medical Center
Erin R. Kesel: University of Rochester Medical Center
Janna Bates: University of Rochester Medical Center
Casey Payne: University of Rochester Medical Center
Devin Chandler-Militello: University of Rochester Medical Center
Abdellatif Benraiss: University of Rochester Medical Center
Steven A. Goldman: University of Rochester Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48118-2

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