AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Epigenetics & Chromatin

Martin Philpott¹  Udo Oppermann²  Nurhan Özlü³  Nazlı Ezgi Özkan-Küçük³  Kenan Sevinç⁴  Burcu Özçimen⁴  Deniz Odluyurt⁴  Eray Enüstün⁴  Deniz Uğurlu-Çimen⁴  Deniz Demirtaş⁴  Can Aztekin⁴  Tamer T. Önder⁴ 

[1] Botnar Research Centre, University of Oxford, Oxford, UK;Botnar Research Centre, University of Oxford, Oxford, UK;Centre for Medicine Discovery, University of Oxford, Oxford, UK;Department of Molecular Biology and Genetics, Koc University, 34450, Istanbul, Turkey;School of Medicine, Koc University, 34450, Istanbul, Turkey;

关键词: AF10;    DOT1L;    BioID;    Reprogramming;    iPSC;    H3K79 methylation;   

DOI  :  10.1186/s13072-021-00406-7

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY