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  Inducible histone K-to-M mutations are dynamic tools to probe the physiological role of site-specific histone methylation in vitro and in vivo

Brumbaugh, J., Kim, I. S., Ji, F., Huebner, A. J., Di Stefano, B., Schwarz, B. A., et al. (2019). Inducible histone K-to-M mutations are dynamic tools to probe the physiological role of site-specific histone methylation in vitro and in vivo. Nature Cell Biology, 21(11), 1449-1461. doi:10.1038/s41556-019-0403-5.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-7935-8 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-7936-7
Genre: Journal Article

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 Creators:
Brumbaugh , Justin , Author
Kim, Ik Soo , Author
Ji, Fei, Author
Huebner, Aaron J. , Author
Di Stefano , Bruno , Author
Schwarz, Benjamin A. , Author
Charlton, Jocelyn1, Author              
Coffey, Amy , Author
Choi, Jiho , Author
Walsh, Ryan M. , Author
Schindler, Jeffrey W. , Author
Anselmo, Anthony, Author
Meissner, Alexander1, 2, 3, Author              
Sadreyev, Ruslan I. , Author
Bernstein, Bradley E. , Author
Hock, Hanno , Author
Hochedlinger , Konrad , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA, ou_persistent22              
3Broad Institute of MIT and Harvard, Cambridge, MA, USA, ou_persistent22              

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 Abstract: Development and differentiation are associated with profound changes to histone modifications, yet their in vivo function remains incompletely understood. Here, we generated mouse models expressing inducible histone H3 lysine-to-methionine (K-to-M) mutants, which globally inhibit methylation at specific sites. Mice expressing H3K36M developed severe anaemia with arrested erythropoiesis, a marked haematopoietic stem cell defect, and rapid lethality. By contrast, mice expressing H3K9M survived up to a year and showed expansion of multipotent progenitors, aberrant lymphopoiesis and thrombocytosis. Additionally, some H3K9M mice succumbed to aggressive T cell leukaemia/lymphoma, while H3K36M mice exhibited differen-tiation defects in testis and intestine. Mechanistically, induction of either mutant reduced corresponding histone trimethylation patterns genome-wide and altered chromatin accessibility as well as gene expression landscapes. Strikingly, discontinuation of transgene expression largely restored differentiation programmes. Our work shows that individual chromatin modifications are required at several specific stages of differentiation and introduces powerful tools to interrogate their roles in vivo.

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Language(s): eng - English
 Dates: 2019-11
 Publication Status: Published in print
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 Identifiers: DOI: 10.1038/s41556-019-0403-5
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Macmillan Magazines Ltd.
Pages: 13 Volume / Issue: 21 (11) Sequence Number: - Start / End Page: 1449 - 1461 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310