PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX
- Erwan Delbarre1,6,
- Kristina Ivanauskiene1,6,
- Jane Spirkoski1,6,
- Akshay Shah1,
- Kristin Vekterud1,
- Jan Øivind Moskaug1,
- Stig Ove Bøe2,
- Lee H. Wong3,
- Thomas Küntziger4 and
- Philippe Collas1,5
- 1Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway;
- 2Department of Medical Biochemistry, Oslo University Hospital, 0027 Oslo, Norway;
- 3Department of Biochemistry and Molecular Biology, School of Biomedical Science, Monash University, Clayton, Victoria 3800, Australia;
- 4Department of Oral Biology, University of Oslo, 0316 Oslo, Norway;
- 5Norwegian Center for Stem Cell Research, Oslo University Hospital, 0027 Oslo, Norway
- Corresponding authors: erwan.delbarre{at}medisin.uio.no; philc{at}medisin.uio.no
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↵6 These authors contributed equally to this work.
Abstract
Maintenance of chromatin homeostasis involves proper delivery of histone variants to the genome. The interplay between different chaperones regulating the supply of histone variants to distinct chromatin domains remains largely undeciphered. We report a role of promyelocytic leukemia (PML) protein in the routing of histone variant H3.3 to chromatin and in the organization of megabase-size heterochromatic PML-associated domains that we call PADs. Loss of PML alters the heterochromatic state of PADs by shifting the histone H3 methylation balance from K9me3 to K27me3. Loss of PML impairs deposition of H3.3 by ATRX and DAXX in PADs but preserves the H3.3 loading function of HIRA in these regions. Our results unveil an unappreciated role of PML in the large-scale organization of chromatin and demonstrate a PML-dependent role of ATRX/DAXX in the deposition of H3.3 in PADs. Our data suggest that H3.3 loading by HIRA and ATRX-dependent H3K27 trimethylation constitute mechanisms ensuring maintenance of heterochromatin when the integrity of these domains is compromised.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.215830.116.
- Received September 12, 2016.
- Accepted March 15, 2017.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
