Spatial partitioning of NSD2 deposits H3K36me2 as an active histone mark to promote repetitive sequence expression [CUT&Tag]

Here, we identify TOP1 as a critical recruiter of the H3K36me2 methyltransferase NSD2 to gene bodies. Disruption of the TOP1–NSD2 interaction reduces H3K36me2 at gene bodies, impairs RNA Polymerase II release, and represses transcription.

Remarkably, loss of this recruitment increases H3K36me2 at repetitive sequences, licensing their aberrant transcriptional activation. Subsequently, we identify MTA1 as a principal recruiter of NSD2 at these repetitive sequences through the recognition of consensus sequence GATC. Together, we demonstrate that TOP1 and MTA1 orchestrate NSD2 binding to direct its genomic distribution.