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Nat Cell Biol. 2019 Nov;21(11):1449-1461. doi: 10.1038/s41556-019-0403-5. Epub 2019 Oct 28.

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 J1,2,3,4,5,6,7, Kim IS3,8,9, Ji F1,6,10, Huebner AJ1,2,3,4,5,6, Di Stefano B1,2,3,4,5,6, Schwarz BA1,2,3,4,5,6, Charlton J4,11, Coffey A1,2,3,4,5,6, Choi J1,2,3,4,5,6, Walsh RM1,2,3,4,5,6, Schindler JW2,3,5,6, Anselmo A1,6,10, Meissner A4,11,9, Sadreyev RI1,6,8, Bernstein BE3,8,9, Hock H12,13,14,15, Hochedlinger K16,17,18,19,20,21,22,23.

Author information

1
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
2
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
3
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
4
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
5
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
6
Harvard Medical School, Boston, MA, USA.
7
Department of Molecular, Cellular, and Developmental Biology, University of Colorado-Boulder, Boulder, CO, USA.
8
Department of Pathology, Harvard Medical School, Boston, MA, USA.
9
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
10
Department of Genetics, Harvard Medical School, Boston, MA, USA.
11
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.
12
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. Hock.Hanno@mgh.harvard.edu.
13
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Hock.Hanno@mgh.harvard.edu.
14
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Hock.Hanno@mgh.harvard.edu.
15
Harvard Medical School, Boston, MA, USA. Hock.Hanno@mgh.harvard.edu.
16
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. khochedlinger@mgh.harvard.edu.
17
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. khochedlinger@mgh.harvard.edu.
18
Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. khochedlinger@mgh.harvard.edu.
19
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. khochedlinger@mgh.harvard.edu.
20
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. khochedlinger@mgh.harvard.edu.
21
Harvard Medical School, Boston, MA, USA. khochedlinger@mgh.harvard.edu.
22
Department of Genetics, Harvard Medical School, Boston, MA, USA. khochedlinger@mgh.harvard.edu.
23
Broad Institute of MIT and Harvard, Cambridge, MA, USA. khochedlinger@mgh.harvard.edu.

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 differentiation 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.

PMID:
31659274
PMCID:
PMC6858577
[Available on 2020-04-28]
DOI:
10.1038/s41556-019-0403-5
[Indexed for MEDLINE]

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