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组蛋白变体H3.3在端粒处提供异染色质H3赖氨酸9三甲基化标记。

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

作者信息

Udugama Maheshi, M Chang Fiona T, Chan F Lyn, Tang Michelle C, Pickett Hilda A, R McGhie James D, Mayne Lynne, Collas Philippe, Mann Jeffrey R, Wong Lee H

机构信息

Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.

Department of Zoology, University of Melbourne, Parkville, Victoria 3052, Australia.

出版信息

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

DOI:10.1093/nar/gkv847
PMID:26304540
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4666390/
Abstract

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.

摘要

除了作为活跃基因的一个标志外，组蛋白变体H3.3还由ATRX沉积在包括端粒在内的抑制性染色质区域。目前尚不清楚H3.3如何促进异染色质组装。我们发现H3.3被靶向进行K9三甲基化，以在端粒处建立富含三甲基化H3.3K9的异染色质状态。在H3f3a(-/-)和H3f3b(-/-)小鼠胚胎干细胞（ESC）中，H3.3缺乏导致端粒处H3K9me3、H4K20me3和ATRX水平降低。当用G-四链体（G4）DNA结合配体处理或通过ASF1缺失使端粒受损时，H3f3b(-/-)细胞显示出端粒损伤和姐妹染色单体交换（t-SCE）活性增加。在H3f3b(-/-)细胞中过表达野生型H3.3（而非H3.3K9突变体）可增加端粒处H3K9三甲基化水平，并抑制由G4配体诱导的t-SCE活性。这项研究证明了H3.3K9三甲基化在端粒异染色质形成中的重要性。它为H3.3在维持哺乳动物组成型异染色质完整性中的功能提供了见解，进一步说明了其在介导基因组转录记忆中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/6d5a600ef021/gkv847fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/f14e354a1fcb/gkv847fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/8a99c6c805ee/gkv847fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/2d2645f27521/gkv847fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/3d356dc43d66/gkv847fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/6d5a600ef021/gkv847fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/f14e354a1fcb/gkv847fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/8a99c6c805ee/gkv847fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/2d2645f27521/gkv847fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/3d356dc43d66/gkv847fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5c6/4666390/6d5a600ef021/gkv847fig5.jpg

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