DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility

Abstract

During neuronal differentiation, the transcriptional profile and the epigenetic context of neural committed cells is subject to significant rearrangements, but a systematic quantification of global histone modification changes is still missing. Here, we show that H3K79me2 increases and H3K27ac decreases globally during in-vitro neuronal differentiation of murine embryonic stem cells. DOT1L mediates all three degrees of methylation of H3K79 and its enzymatic activity is critical to modulate cellular differentiation and reprogramming. In this context, we find that inhibition of DOT1L in neural progenitor cells biases the transcriptional state towards neuronal differentiation, resulting in transcriptional upregulation of genes marked with H3K27me3 on the promoter region. We further show that DOT1L inhibition affects accessibility of SOX2-bound enhancers and impairs SOX2 binding in neural progenitors. Our work provides evidence that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs.

Histone methyltransferase DOT1L controls state‐specific identity during B cell differentiation

“…These findings show that DOT1L‐mediated H3K79me2 is a mark of many active genes in B cells, but suggest that only a small fraction of these genes requires H3K79me2 for maintenance of gene expression, since only a subset of the active genes was downregulated in Dot1L ‐KO B cells. Similar observations in transcriptome changes were also made in CD8 + T cells lacking DOT1L as well as upon DOT1L inhibition in mouse ES cells and during human cellular reprogramming (Kwesi‐Maliepaard et al , 2020; Ferrari et al , 2020; Kim et al , 2021).…”

“…The observation that Ezh2 is normally H3K79‐dimethylated and downregulated in Dot1L ‐KO B cells, and that Dot1L and Ezh2 are co‐regulated in B cells indicates that DOT1L might promote repression of PRC2 targets by maintaining expression of Ezh2 . Alternatively, DOT1L might affect a subset of PRC2 targets by altered activity of co‐repressor complexes, as has been suggested for DOT1L in mouse ES cell differentiation (Ferrari et al , 2020). Finally, additional factors controlled by DOT1L may impact differentiation of B cells (e.g.…”

DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome

“…H3K79me2/3 are enriched at certain intronic enhancers in leukemia cell lines and regulate future deposition of H3K27ac ( Godfrey et al., 2019 ), a modification associated with enhancer activity. In neural differentiation, DOT1Li decreased accessibility of a subset of enhancers ( Ferrari et al., 2020 ). In support of further epigenetic alterations, both upregulated and downregulated genes can be decorated by H3K79me2 before DOT1L depletion in development of the cerebral cortex ( Franz et al., 2019 ).…”

Autophagy-cell death balance is maintained by Polycomb-mediated regulation during stem cell differentiation

“…As our studies indicated that Dram1 upregulation leads to distinct effects on autophagy and cell death in mESCs vs differentiating cells, we analysed the enrichment of activating and repressive chromatin modifications on the Dram1 promoter in these cells. ChIP-Seq data (GSE135318) [51], revealed that the Dram1 promoter is enriched with primarily the H3K27me3 mark in mESCs. In neural progenitor cells (NPCs) however, we observed the enrichment of H3K27me3 as well as H3K4me3 at the Dram1 promoter (Figure S3d).…”