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1.
Science ; 372(6537): 91-94, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795458

RESUMO

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.


Assuntos
Reparo do DNA , Genoma Humano , Instabilidade Genômica , Neurônios/metabolismo , Envelhecimento/genética , Dano ao DNA , DNA Intergênico , Desoxiuridina/análogos & derivados , Desoxiuridina/metabolismo , Células-Tronco Embrionárias , Histonas/metabolismo , Humanos , Mitose , Mutação , Doenças do Sistema Nervoso/genética , Neurônios/citologia , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/metabolismo , Análise de Sequência de DNA , Transcrição Gênica
2.
Elife ; 82019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30730291

RESUMO

Comparative analyses of neuronal phenotypes in closely related species can shed light on neuronal changes occurring during evolution. The study of post-mortem brains of nonhuman primates (NHPs) has been limited and often does not recapitulate important species-specific developmental hallmarks. We utilize induced pluripotent stem cell (iPSC) technology to investigate the development of cortical pyramidal neurons following migration and maturation of cells grafted in the developing mouse cortex. Our results show differential migration patterns in human neural progenitor cells compared to those of chimpanzees and bonobos both in vitro and in vivo, suggesting heterochronic changes in human neurons. The strategy proposed here lays the groundwork for further comparative analyses between humans and NHPs and opens new avenues for understanding the differences in the neural underpinnings of cognition and neurological disease susceptibility between species.


Assuntos
Neurônios/citologia , Pan paniscus/fisiologia , Pan troglodytes/fisiologia , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular/genética , Dendritos/metabolismo , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/transplante , Especificidade da Espécie
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