Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres.
Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres.
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DOI：
10.1093/nar/gkv847
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发表时间：
2015-12-02
影响因子：
14.9
通讯作者：
Wong LH
中科院分区：
文献类型：
--
作者：
Udugama M;M Chang FT;Chan FL;Tang MC;Pickett HA;R McGhie JD;Mayne L;Collas P;Mann JR;Wong LH
除了作为活性基因的标志外，组蛋白变体H3.3还通过ATRX沉积在抑制性染色质区域，包括端粒。目前还不清楚H3.3如何促进异染色质组装。我们表明H3.3是K9三甲基化的目标，以建立端粒处富含三甲基化H3.3K9的异染色质状态。在H3 f3 a −/−和H3 f3 b −/−小鼠胚胎干细胞（ESC）中，H3.3缺陷导致端粒处H3 K9 me 3、H4 K20 me 3和ATRX水平降低。H3 f3 b −/−细胞显示端粒损伤和姐妹染色单体交换（t-SCE）活性的水平增加时，端粒与G-四链体（G4）DNA结合配体或ASF 1耗尽的治疗受到损害。野生型H3.3（但不是H3.3K9突变体）在H3 f3 b −/−细胞中的过表达增加了端粒处的H3 K9三甲基化水平，并抑制了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。它提供了对H3.3在维持哺乳动物组成型异染色质完整性中的功能的见解，增加了其在基因组中介导转录记忆中的作用。
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.