RESUMEN
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.
Asunto(s)
Envejecimiento , MicroARNs , Neuroglía , Factores de Transcripción , Humanos , Neuroglía/metabolismo , Neuroglía/citología , Envejecimiento/genética , Envejecimiento/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , MicroARNs/genética , MicroARNs/metabolismo , Senescencia Celular/genética , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre/metabolismo , Células Madre/citología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Adulto , Redes Reguladoras de Genes , Proliferación Celular/genética , Regulación del Desarrollo de la Expresión Génica , Perfilación de la Expresión GénicaRESUMEN
Neural stem cells (NSCs) in the developing and postnatal brain have distinct positional identities that dictate the types of neurons they generate. Although morphogens initially establish NSC positional identity in the neural tube, it is unclear how such regional differences are maintained as the forebrain grows much larger and more anatomically complex. We found that the maintenance of NSC positional identity in the murine brain requires a mixed-lineage leukemia 1 (Mll1)-dependent epigenetic memory system. After establishment by sonic hedgehog, ventral NSC identity became independent of this morphogen. Even transient MLL1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. Thus, spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain.