C-Jun recruits the NSL complex to regulate its target gene expression by modulating H4K16 acetylation and promoting the release of the repressive NuRD complex.

The proto-oncogene c-Jun plays essential roles in various cellular processes, including cell proliferation, cell differentiation, and cellular apoptosis. Enormous efforts have been made to understand the mechanisms regulating c-Jun activation. The males absent on the first (MOF)-containing non-specific lethal (NSL) complex has been shown to positively regulate gene expression. However, the biological function of the NSL complex is largely unknown. Here we present evidence showing that c-Jun recruits the NSL complex to c-Jun target genes upon activation. The NSL complex catalyzes H4K16 acetylation at c-Jun target genes, thereby promoting c-Jun target gene transcription. More interestingly, we also found that the NSL complex promotes the release of the repressive NuRD complex from c-Jun target genes, thus activating c-Jun. Our findings not only reveal a new mechanism regulating c-Jun activation, but also identify the NSL complex as a c-Jun co-activator in c-Jun-regulated gene expression, expanding our knowledge of the function of the NSL complex in gene expression regulation.