Histone editing elucidates the functional roles of H3K27 methylation and acetylation in mammals Research Letter

Authors: Sankar, A.; Mohammad, F.; Sundaramurthy, A. K.; Wang, H.; Lerdrup, M.; Tatar, T.; Helin, K.
Title: Histone editing elucidates the functional roles of H3K27 methylation and acetylation in mammals
Abstract: Posttranslational modifications of histones (PTMs) are associated with specific chromatin and gene expression states1,2. Although studies in Drosophila melanogaster have revealed phenotypic associations between chromatin-modifying enzymes and their histone substrates, comparable studies in mammalian models do not exist3–5. Here, we use CRISPR base editing in mouse embryonic stem cells (mESCs) to address the regulatory role of lysine 27 of histone H3 (H3K27), a substrate for Polycomb repressive complex 2 (PRC2)-mediated methylation and CBP/EP300-mediated acetylation6,7. By generating pan-H3K27R (pK27R) mutant mESCs, where all 28 alleles of H3.1, H3.2 and H3.3 have been mutated, we demonstrate similarity in transcription patterns of genes and differentiation to PRC2-null mutants. Moreover, H3K27 acetylation is not essential for gene derepression linked to loss of H3K27 methylation, or de novo activation of genes during cell-fate transition to epiblast-like cells (EpiLCs). In conclusion, our results show that H3K27 is an essential substrate for PRC2 in mESCs, whereas other PTMs in addition to H3K27 acetylation are likely involved in mediating CBP/EP300 function. Our work demonstrates the feasibility of large-scale multicopy gene editing to interrogate histone PTM function in mammalian cells. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: methylation; genetics; mouse; animal; metabolism; animals; mice; protein processing; protein processing, post-translational; histone; chromatin; mammal; drosophila melanogaster; mammals; histones; acetylation; polycomb repressive complex 2
Journal Title: Nature Genetics
Volume: 54
Issue: 6
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2022-06-01
Start Page: 754
End Page: 760
Language: English
DOI: 10.1038/s41588-022-01091-2
PUBMED: 35668298
PROVIDER: scopus
Notes: Article -- Export Date: 1 July 2022 -- Source: Scopus
Citation Impact
MSK Authors
  1. Kristian Helin
    31 Helin
  2. Hua Wang
    7 Wang