ATAC-sequencing data of THP-1 cells after the knockout of MSL1

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 its catalytic activity and function depending on its associated proteins, and that it, as part of the NSL complex, catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival. We compared ATAC-seq profiles of the human acute myeloid leukemia cell line THP-1 with and without the knockout of MSL1 protein. Cells transduced with either a non-targeting sgRNA (sgNegCtrl, 2 biological replicates) or sgRNAs inducing knockout of MSL1 (sgMSL1, 2 biological replicates).