Control of genetic stability by a new heterochromatin compaction pathway involving the Tip60 histone acetyltransferase.
Control of genetic stability by a new heterochromatin compaction pathway involving the Tip60 histone acetyltransferase.
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DOI：
10.1091/mbc.e15-05-0316
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发表时间：
2016-02-15
影响因子：
3.3
通讯作者：
Escaffit F
中科院分区：
文献类型：
--
作者：
Grézy A;Chevillard-Briet M;Trouche D;Escaffit F
鉴定了哺乳动物臂间异染色质的一种新的压实途径，其依赖于Tip60的H4K12ac，可能随后是BRD2的募集，因此染色质压实，这可以有助于遗传稳定性。着丝粒周异染色质是一种高度致密的结构，在有丝分裂中染色体的精确分离是必需的。在哺乳动物中，它依赖于Suv39H酶对组蛋白H3K9的甲基化，这为HP 1蛋白提供了一个对接位点，因此介导了异染色质压缩。在这里，我们表明，当这种正常的压实途径是有缺陷的，组蛋白乙酰转移酶Tip60被招募到臂间异染色质，在那里它介导组蛋白H4K12的乙酰化。此外，在这种情况下，Tip60的缺失导致卫星转录的去抑制，臂间异染色质的解压缩，以及有丝分裂中染色体分离的缺陷。最后，我们表明，BRD2，一个双溴结构域的蛋白质，结合H4K12ac，phenocopies Tip60消耗消耗异染色质解压缩和染色体分离的缺陷。综合这些结果，我们确定了一个依赖于Tip60的哺乳动物臂间异染色质的新压缩途径，该途径可能依赖于H4K12乙酰化的BRD2募集。我们认为，在许多人类肿瘤中观察到的Tip60低表达可以通过有缺陷的臂间异染色质促进遗传不稳定性。
A new compaction pathway of mammalian pericentric heterochromatin is identified, which relies on H4K12ac by Tip60, probably followed by recruitment of BRD2, and therefore chromatin compaction, which can contribute to genetic stability. Pericentric heterochromatin is a highly compacted structure required for accurate chromosome segregation in mitosis. In mammals, it relies on methylation of histone H3K9 by Suv39H enzymes, which provides a docking site for HP1 proteins, therefore mediating heterochromatin compaction. Here we show that, when this normal compaction pathway is defective, the histone acetyltransferase Tip60 is recruited to pericentric heterochromatin, where it mediates acetylation of histone H4K12. Furthermore, in such a context, depletion of Tip60 leads to derepression of satellite transcription, decompaction of pericentric heterochromatin, and defects in chromosome segregation in mitosis. Finally, we show that depletion of BRD2, a double bromodomain–containing protein that binds H4K12ac, phenocopies the Tip60 depletion with respect to heterochromatin decompaction and defects in chromosome segregation. Taking the results together, we identify a new compaction pathway of mammalian pericentric heterochromatin relying on Tip60 that might be dependent on BRD2 recruitment by H4K12 acetylation. We propose that the underexpression of Tip60 observed in many human tumors can promote genetic instability via defective pericentric heterochromatin.