DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome.
Stem Cell Reports
; 17(2): 384-396, 2022 02 08.
Article
em En
| MEDLINE
| ID: mdl-34995500
ABSTRACT
Inhibiting the histone 3 lysine 79 (H3K79) methyltransferase, disruptor of telomeric silencing 1-like (DOT1L), increases the efficiency of reprogramming somatic cells to induced pluripotent stem cells (iPSCs). Here, we find that, despite the enrichment of H3K79 methylation on thousands of actively transcribed genes in somatic cells, DOT1L inhibition (DOT1Li) does not immediately cause the shutdown of the somatic transcriptional profile to enable transition to pluripotency. Contrary to the prevalent view, DOT1Li promotes iPSC generation beyond the mesenchymal to epithelial transition and even from already epithelial cell types. DOT1Li is most potent at the midpoint of reprogramming in part by repressing Nfix that persists at late stages of reprogramming. Importantly, regulation of single genes cannot substitute for DOT1Li, demonstrating that H3K79 methylation has pleiotropic effects in maintaining cell identity.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Histona-Lisina N-Metiltransferase
/
Transcriptoma
Limite:
Animals
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos