Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells
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Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells. / Mariani, John N.; Mansky, Benjamin; Madsen, Pernille M.; Salinas, Dennis; Kesmen, Deniz; Huynh, Nguyen P.T.; Kuypers, Nicholas J.; Kesel, Erin R.; Bates, Janna; Payne, Casey; Chandler-Militello, Devin; Benraiss, Abdellatif; Goldman, Steven A.
I: Nature Communications, Bind 15, Nr. 1, 3873, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells
AU - Mariani, John N.
AU - Mansky, Benjamin
AU - Madsen, Pernille M.
AU - Salinas, Dennis
AU - Kesmen, Deniz
AU - Huynh, Nguyen P.T.
AU - Kuypers, Nicholas J.
AU - Kesel, Erin R.
AU - Bates, Janna
AU - Payne, Casey
AU - Chandler-Militello, Devin
AU - Benraiss, Abdellatif
AU - Goldman, Steven A.
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
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.
U2 - 10.1038/s41467-024-48118-2
DO - 10.1038/s41467-024-48118-2
M3 - Journal article
C2 - 38719882
AN - SCOPUS:85192354441
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3873
ER -
ID: 392445523