AF9 YEATS Domain Links Histone Acetylation to DOT1L-Mediated H3K79 Methylation

The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here, we show that the AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known acetyllysine readers. ChIP-seq experiments revealed a strong colocalization of AF9 and H3K9 acetylation genome-wide, which is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identified the evolutionarily conserved YEATS domain as a novel acetyllysine-binding module and established a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control. [Display omitted] •The YEATS domains constitute a novel family of readers for histone acetylation•AF9 YEATS binds to histone H3K9 acetylation via a novel recognition mechanism•AF9 colocalizes with H3K9 acetylation genome-wide•AF9 recruits DOT1L to deposit H3K79 methylation on active chromatin The evolutionarily conserved YEATS domain is a novel acetyllysine-binding module and binds strongly to histone H3K9 acetylation. It serves as a direct link between histone acetylation and DOT1L-mediated H3K79 methylation in transcription control.