| Autor: |
Kenan Sevinç, Tamer T. Onder, Martin Philpott, Burcu Özçimen, Nazlı Ezgi Özkan-Küçük, Udo Oppermann, Deniz Odluyurt, Nurhan Özlü, Can Aztekin, Eray Enustun, Deniz Demirtaş, Deniz Uğurlu-Çimen |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
SummaryThe histone H3 lysine 79 (H3K79) methyltransferase DOT1L is a key chromatin-based barrier to somatic cell reprogramming. However, the mechanisms by which DOT1L safeguards cell identity and somatic-specific transcriptional programs remain unknown. Here, we employed a proteomic approach using proximity-based labeling to identify DOT1L-interacting proteins and investigated their effects on reprogramming. Among DOT1L interactors, suppression of AF10 (MLLT10) via RNA interference or CRISPR/Cas9, significantly increases reprogramming efficiency. In somatic cells and induced pluripotent stem cells (iPSCs) higher order H3K79 methylation is dependent on AF10 expression. In AF10 knockout cells, re-expression wildtype AF10, but not a mutant defective in DOT1L binding, rescues overall H3K79 methylation and reduces reprogramming efficiency. Transcriptomic analyses during reprogramming show that AF10 suppression results in downregulation of fibroblast-specific genes and accelerates the activation of pluripotency-associated genes. Our findings establish AF10 as a novel barrier to reprogramming by regulating H3K79 methylation and thereby sheds light on the mechanism by which cell identity is maintained in somatic cells. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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