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

Epigenetics Chromatin. 2021 Jul 2;14(1):32. doi: 10.1186/s13072-021-00406-7.


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.

Keywords: AF10; BioID; DOT1L; H3K79 methylation; Reprogramming; iPSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cellular Reprogramming*
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Methylation
  • Proteomics
  • Transcription Factors* / metabolism


  • MLLT10 protein, human
  • Transcription Factors
  • DOT1L protein, human
  • Histone-Lysine N-Methyltransferase