A PWWP Domain of histone-lysine N-methyltransferase NSD2 binds to dimethylated lys-36 of histone H3 and regulates NSD2 function at chromatin

Abstract

The readout of histone modifications plays a critical role in chromatin-regulated processes. Dimethylation at Lys-36 onhistone H3 (H3K36me2) is associated with actively transcribed genes, and global up-regulation of this modification is associated with several cancers. However, the molecular mechanism by which H3K36me2 is sensed and transduced to downstream biological outcomes remains unclear. Here weidentifya PWWP domain within the histone lysine methyltransferase and oncopro-tein NSD2 that preferentially binds to nucleosomes containing H3K36me2. In cells, the NSD2 PWWP domain interaction with H3K36me2 plays a role in stabilizing NSD2 at chromatin. Furthermore, NSD2's ability to induce global increases in H3K36me2 via its enzymatic activity, and consequently promote cellular proliferation, is compromised by mutations within the PWWP domain that specifically abrogate H3K36me2-recognition. Together, our results identify a pivotal role for NSD2 binding to its catalytic product in regulating its cellular functions, and suggest a model for how this interaction may facilitate epigenetic spreading and propagation of H3K36me2.