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

Adam Karoutas, Witold Szymanski, Tobias Rausch, Sukanya Guhathakurta, Eva A. Rog-Zielinska, Remi Peyronnet, Janine Seyfferth, Hui Ru Chen, Rebecca de Leeuw, Benjamin Herquel, Hiroshi Kimura, Gerhard Mittler, Peter Kohl, Ohad Medalia, Jan O. Korbel, Asifa Akhtar

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish
Pages (from-to)1248-1260
Number of pages13
JournalNature Cell Biology
Volume21
Issue number10
DOIs
StatePublished - 1 Oct 2019

ASJC Scopus subject areas

  • Cell Biology

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