Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcriptional regulation and cellular homeostasis [TMT11plex whole proteome analysis]

ABSTRACT: Histone acetylation is associated with open chromatin and transcriptionally active genes. Specifically, acetylation of lysine 16 on histone H4 (H4K16ac) has been shown to prevent the assembly of nucleosomal arrays in vitro. This modification is catalyzed by the MYST-family histone acetyltransferase KAT8 (also known as MOF and MYST1), which is part of two distinct chromatin-associated complexes: NSL and MSL. While extensively studied in Drosophila, the functions of H4K16ac and the two KAT8-containing complexes in mammalian cells are not well understood. Here, we demonstrate a surprising complex-dependent activity of KAT8. We found that KAT8 catalyzes H4K5 and H4K8 acetylation as part of the NSL complex, whereas it catalyzes the bulk of H4K16 acetylation as part of the MSL complex. Furthermore, we show that the core proteins of the MSL complex and H4K16ac are not required for cell proliferation and global chromatin accessibility, whereas the NSL complex is essential for cell survival, as it is enriched at the promoters of housekeeping genes and is required for their transcription initiation. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins, and that, as part of the NSL complex, it catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Pavel Shliaha  

LAB HEAD: Ole N Jensen

PROVIDER: PXD023865 | Pride | 2021-06-29

REPOSITORIES: Pride