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The NSL complex maintains nuclear architecture stability via lamin A/C acetylation

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Karoutas,  Adam
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Szymanski,  Witold
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Guhathakurta,  Sukanya
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Seyfferth,  Janine
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Chen,  Hui-Ru
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Mittler,  Gerhard
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Medalia,  Ohad
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Akhtar,  Asifa
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Karoutas, A., Szymanski, W., Rausch, T., Guhathakurta, S., Rog-Zielinska, E. A., Peyronnet, R., et al. (2019). The NSL complex maintains nuclear architecture stability via lamin A/C acetylation. Nature Cell Biology, 21, 1248-1260. doi:org/10.1038/s41556-019-0397-z.


Cite as: http://hdl.handle.net/21.11116/0000-0005-1C34-2
Abstract
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.