AF10 (MLLT10) Prevents Somatic Cell Reprogramming Through Regulation of DOT1L-mediated H3K79 Methylation

Overview

Journal Epigenetics Chromatin

Publisher Biomed Central

Specialties Biochemistry
Genetics

Date 2021 Jul 3

PMID 34215314

Citations 8

Authors

Deniz Ugurlu-Cimen

Deniz Odluyurt

Kenan Sevinc

Nazli Ezgi Ozkan-Kucuk

Burcu Ozcimen

Deniz Demirtas

Eray Enustun

Can Aztekin

Martin Philpott

Udo Oppermann

Nurhan Ozlu

Tamer T Onder

Affiliations

Soon will be listed here.

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.

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