Research Project: DOT11 HİSTON MENTİL-TRANSFERAZININ YENİDEN PROGRAMLAMA SIRASINDA ETKİLEŞİM HALİNDE BULUNDUĞU PROTEİNLERİN BELİRLENMESİ
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Contributors
Funders
ID
TB.00249
Authors
Önder, Tamer Tevfik
Faculty Member
Publications
AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation
(BioMed Central, 2021) Demirtaş, Deniz; Enüstün, Eray; Küçük, Nazlı Ezgi Özkan; Önder, Tamer Tevfik; Özçimen, Burcu; Sevinç, Kenan; Uğurlu Çimen, Deniz; Odluyurt, Deniz; Aztekin, Can; Philpott, Martin; Oppermann, Udo; Department of Molecular Biology and Genetics; Graduate School of Health Sciences; Graduate School of Sciences and Engineering; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; College of Sciences; GRADUATE SCHOOL OF HEALTH SCIENCES; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; Research Center; SCHOOL OF MEDICINE
Background: the 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. Results: 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 knock-out cells, re-expression wild-type AF10, but not a DOT1L binding-impaired mutant, 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. Conclusions: 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.
