The NSL complex maintains nuclear architecture stability via lamin A/C acetylation
The NSL complex maintains nuclear architecture stability via lamin A/C acetylation
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DOI：
10.1038/s41556-019-0397-z
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发表时间：
2019-10-01
影响因子：
21.3
通讯作者：
Akhtar, Asifa
中科院分区：
文献类型：
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作者：
Karoutas, Adam;Szymanski, Witold;Akhtar, Asifa
虽然核纤层异常是人类疾病的标志，但它们与表观遗传调节因子和精确的表观遗传景观的相互作用仍然知之甚少。在这里，我们表明，赖氨酸乙酰转移酶MOF或其相关的NSL复合物成员KANSL 2或KANSL 3的损失导致随机积累的核异常与基因组不稳定模式，包括chromothripsis。基于SILAC的MOF和KANSL 2乙酰组鉴定核纤层蛋白A/C为MOF的乙酰化靶标。HDAC抑制或乙酰化模拟核纤层蛋白A衍生物拯救在MOF缺陷细胞中观察到的核异常。从机制上讲，核纤层蛋白A/C乙酰化的丧失导致其溶解度增加、磷酸化动力学缺陷和核机械稳定性受损。我们发现，核异常包括EZH 2依赖性组蛋白H3赖氨酸27三甲基化和新生转录的损失。我们将这种改变的表观遗传景观称为“核异常中的异染色质富集”（HENA）。总的来说，NSL复合物依赖性核纤层蛋白A/C乙酰化提供了维持核结构和基因组完整性的机制。
While nuclear lamina abnormalities are hallmarks of human diseases, their interplay with epigenetic regulators and precise epigenetic landscape remain poorly understood. Here, we show that loss of the lysine acetyltransferase MOF or its associated NSL-complex members KANSL2 or KANSL3 leads to a stochastic accumulation of nuclear abnormalities with genomic instability patterns including chromothripsis. SILAC-based MOF and KANSL2 acetylomes identified lamin A/C as an acetylation target of MOF. HDAC inhibition or acetylation-mimicking lamin A derivatives rescue nuclear abnormalities observed in MOF-deficient cells. Mechanistically, loss of lamin A/C acetylation resulted in its increased solubility, defective phosphorylation dynamics and impaired nuclear mechanostability. We found that nuclear abnormalities include EZH2-dependent histone H3 Lys 27 trimethylation and loss of nascent transcription. We term this altered epigenetic landscape "heterochromatin enrichment in nuclear abnormalities" (HENA). Collectively, the NSL-complex-dependent lamin A/C acetylation provides a mechanism that maintains nuclear architecture and genome integrity.