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

Nat Commun. 2024 May 8;15(1):3873. doi: 10.1038/s41467-024-48118-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aging* / genetics
  • Aging* / metabolism
  • Cell Proliferation / genetics
  • Cellular Senescence / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Neuroglia* / cytology
  • Neuroglia* / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • Transcription Factors
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc