DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity

Abstract

Histone-modifying enzymes function as part of protein complexes that alter the accessibility of chromatin to elicit differential gene expression patterns. Dot1L, the sole histone H3 lysine (K) 79 (H3K79) methyltransferase, is associated with proteins that recognize specific histone modifications and target Dot1L to particular chromatin contexts. Here we find that depletion of the Dot1L interacting protein AF10, which recognizes unmodified H3K27, mimics Dot1L catalytic inhibition to increase the efficiency of reprogramming somatic cells to induced pluripotent stem cells (iPSCs). AF10 deletion results in almost no steady state transcriptional changes yet is responsible for half of the Dot1L iPSC reprogramming phenotype. In contrast, reduced levels of Dot1L interactors AF9 and ENL that recognize H3 acetylation decrease iPSC generation. Despite the opposite effects in reprogramming of Dot1L interacting proteins with differing histone reader specificity, we find that the AF10-histone interaction domain is dispensable for increased iPSC generation. Instead, the AF10-Dot1L interaction domain that potentiates H3K79 di- and tri-methylation is a barrier to pluripotency acquisition. Taken together we reveal a key role for higher order gene body histone methylation in safeguarding cell identity.

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

“…The latter proteins are also present in the Super Elongation Complex (SEC) [ 26 ]. The fact that AF9, AF17 and ENL had no effect in reprogramming points to a specific role for AF10 in this process, a finding corroborated in recent studies of mouse reprogramming [ 27 ]. This finding also suggests that DOT1L’s role in suppressing cellular reprogramming may be largely independent of its association with transcriptional elongation and its effect on RNA Polymerase II processivity [ 28 ].…”

Signals for antigen-independent differentiation of memory CD8+ T cells

“…It would also be interesting to understand what the role is of putative H3K79 methyl 'reader' proteins and DOT1L binding partners in T AIM differentiation, since these factors affect DOT1L output and activity [83,89]. Finally, epigenetic regulators that impact DOT1L activity, including the histone deacetylase HDAC1 and the H2B ubiquitination machinery [83,[90][91][92], are also candidate factors affecting T AIM differentiation.…”