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Cell Rep ; 30(11): 3597-3604.e3, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187532

RESUMO

Cultured pluripotent cells accumulate detrimental chromatin alterations, including DNA methylation changes at imprinted genes known as loss of imprinting (LOI). Although the occurrence of LOI is considered a stochastic phenomenon, here we document a genetic determinant that segregates mouse pluripotent cells into stable and unstable cell lines. Unstable lines exhibit hypermethylation at Dlk1-Dio3 and other imprinted loci, in addition to impaired developmental potential. Stimulation of demethylases by ascorbic acid prevents LOI and loss of developmental potential. Susceptibility to LOI greatly differs between commonly used mouse strains, which we use to map a causal region on chromosome 13 with quantitative trait locus (QTL) analysis. Our observations identify a strong genetic determinant of locus-specific chromatin abnormalities in pluripotent cells and provide a non-invasive way to suppress them. This highlights the importance of considering genetics in conjunction with culture conditions for assuring the quality of pluripotent cells for biomedical applications.


Assuntos
Cromossomos de Mamíferos/genética , Loci Gênicos , Impressão Genômica , Células-Tronco Pluripotentes/metabolismo , Animais , Ácido Ascórbico/farmacologia , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular , Metilação de DNA/genética , Desenvolvimento Embrionário/efeitos dos fármacos , Epigênese Genética , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Embrionárias Murinas/metabolismo , Locos de Características Quantitativas/genética
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