Delbarre Erwan, Ivanauskiene Kristina, Spirkoski Jane, Shah Akshay, Vekterud Kristin, Moskaug Jan Øivind, Bøe Stig Ove, Wong Lee H, Küntziger Thomas, Collas Philippe
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
Department of Medical Biochemistry, Oslo University Hospital, 0027 Oslo, Norway.
Genome Res. 2017 Jun;27(6):913-921. doi: 10.1101/gr.215830.116. Epub 2017 Mar 24.
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.
染色质稳态的维持涉及组蛋白变体向基因组的正确递送。不同伴侣蛋白之间调节向不同染色质结构域供应组蛋白变体的相互作用在很大程度上仍未被破解。我们报告了早幼粒细胞白血病（PML）蛋白在组蛋白变体H3.3向染色质的转运以及在我们称为PADs的兆碱基大小的异染色质PML相关结构域的组织中的作用。PML的缺失通过将组蛋白H3甲基化平衡从K9me3转变为K27me3来改变PADs的异染色质状态。PML的缺失损害了ATRX和DAXX在PADs中对H3.3的沉积，但保留了HIRA在这些区域的H3.3加载功能。我们的结果揭示了PML在染色质大规模组织中未被重视的作用，并证明了ATRX/DAXX在PADs中H3.3沉积中的PML依赖性作用。我们的数据表明，HIRA对H3.3的加载以及ATRX依赖性H3K27三甲基化构成了在这些结构域完整性受损时确保异染色质维持的机制。
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