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Nucleic Acids Res. 2015 Dec 2;43(21):10227-37. doi: 10.1093/nar/gkv847. Epub 2015 Aug 24.

Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres.

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Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
Department of Zoology, University of Melbourne, Parkville, Victoria 3052, Australia.
Telomere Length Regulation Group, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, and Norwegian Center for Stem Cell Research, University of Oslo, 0317 Oslo, Norway.
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia


In addition to being a hallmark at active genes, histone variant H3.3 is deposited by ATRX at repressive chromatin regions, including the telomeres. It is unclear how H3.3 promotes heterochromatin assembly. We show that H3.3 is targeted for K9 trimethylation to establish a heterochromatic state enriched in trimethylated H3.3K9 at telomeres. In H3f3a(-/-) and H3f3b(-/-) mouse embryonic stem cells (ESCs), H3.3 deficiency results in reduced levels of H3K9me3, H4K20me3 and ATRX at telomeres. The H3f3b(-/-) cells show increased levels of telomeric damage and sister chromatid exchange (t-SCE) activity when telomeres are compromised by treatment with a G-quadruplex (G4) DNA binding ligand or by ASF1 depletion. Overexpression of wild-type H3.3 (but not a H3.3K9 mutant) in H3f3b(-/-) cells increases H3K9 trimethylation level at telomeres and represses t-SCE activity induced by a G4 ligand. This study demonstrates the importance of H3.3K9 trimethylation in heterochromatin formation at telomeres. It provides insights into H3.3 function in maintaining integrity of mammalian constitutive heterochromatin, adding to its role in mediating transcription memory in the genome.

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