Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcription and cellular homeostasis

Aliaksandra Radzisheuskaya, Pavel V Shliaha, Vasily V Grinev, Daria Shlyueva, Helene Damhofer, Richard Koche, Vladimir Gorshkov, Sergey Kovalchuk, Yingqian Zhan, Keli L Rodriguez, Andrea L Johnstone, Michael-C Keogh, Ronald C Hendrickson, Ole N Jensen, Kristian Helin

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Acetylation of lysine 16 on histone H4 (H4K16ac) is catalyzed by histone acetyltransferase KAT8 and can prevent chromatin compaction in vitro. Although extensively studied in Drosophila, the functions of H4K16ac and two KAT8-containing protein complexes (NSL and MSL) are not well understood in mammals. Here, we demonstrate a surprising complex-dependent activity of KAT8: it catalyzes H4K5ac and H4K8ac as part of the NSL complex, whereas it catalyzes the bulk of H4K16ac as part of the MSL complex. Furthermore, we show that MSL complex proteins and H4K16ac are not required for cell proliferation and chromatin accessibility, whereas the NSL complex is essential for cell survival, as it stimulates transcription initiation at the promoters of housekeeping genes. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins and that, when in the NSL complex, it catalyzes H4K5ac and H4K8ac required for the expression of essential genes.

Original languageEnglish
JournalMolecular Cell
Volume81
Issue number8
Pages (from-to)1749-1765.e8
ISSN1097-2765
DOIs
Publication statusPublished - 15. Apr 2021

Keywords

  • Acetylation
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus/genetics
  • Cell Proliferation/genetics
  • Chromatin/genetics
  • HEK293 Cells
  • HeLa Cells
  • Histone Acetyltransferases/genetics
  • Histones/genetics
  • Homeostasis/genetics
  • Humans
  • K562 Cells
  • Lysine/genetics
  • Male
  • Mice
  • Promoter Regions, Genetic/genetics
  • THP-1 Cells
  • Transcription, Genetic/genetics

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