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

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

EPIGENETICS & CHROMATIN, cilt.14, sa.1, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 14 Sayı: 1
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1186/s13072-021-00406-7
  • Dergi Adı: EPIGENETICS & CHROMATIN
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, EMBASE, MEDLINE, Directory of Open Access Journals
  • Anahtar Kelimeler: AF10, DOT1L, BioID, Reprogramming, iPSC, PLURIPOTENT STEM-CELLS, TRANSCRIPTION ELONGATION, GENE-EXPRESSION, DOT1L, GENERATION, COMPLEX, DOMAIN
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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.