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


Ugurlu-Cimen D., Odluyurt D., Sevinc K., Ozkan-Kucuk N. E. , Ozcimen B. , Demirtas D., ...More

EPIGENETICS & CHROMATIN, vol.14, no.1, 2021 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 14 Issue: 1
  • Publication Date: 2021
  • Doi Number: 10.1186/s13072-021-00406-7
  • Title of Journal : EPIGENETICS & CHROMATIN
  • Keywords: AF10, DOT1L, BioID, Reprogramming, iPSC, PLURIPOTENT STEM-CELLS, TRANSCRIPTION ELONGATION, GENE-EXPRESSION, DOT1L, GENERATION, COMPLEX, DOMAIN

Abstract

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.