The histone methyltransferase NSD3 oncogene triggers ribosomal DNA transcription, interfering with FOSL2 in cancer

Ribosome biogenesis is pervasively enhanced in cancer, and yet, how the expression of ribosomal RNA genes is triggered remains largely unknown. We found that the long isoform of the histone methyltransferase NSD3, NSD3L, one of the most frequently amplified genes in cancer, reshapes the chromatin environment surrounding ribosomal DNA (rDNA), thus triggering rRNA expression. An unbiased mass-spec approach revealed that NSD3L binds several nucleolar proteins and localizes to the nucleolus. NSD3L is essential for the binding of Polymerase I as well as of its activator UBTF (Upstream Binding Transcription Factor) to the entire rDNA locus. Conversely, NSD3L binds to a narrow sequence on rDNA located upstream of the rRNA transcription start site (TSS), displacing FOSL2, a member of the FOS/JUN transcription factor family. Upon NSD3L ablation, FOSL2 increases its binding to this region, leading to reduced rDNA expression. These results suggest a surprising, repressive role for FOSL2 on ribosomal gene expression. We also determined that NSD3L competes with another suppressor of rDNA expression, the histone methyltransferase SUV4-20H, thus impeding the deposition of the repressive histone mark H4K20me3 on rDNA. Therefore, NSD3L balances and counteracts the activities of FOSL2 and SUV4-20H on rDNA, unleashing rDNA synthesis. Accordingly, NSD3L overexpression is associated with enhanced expression of nucleolar genes in several tumor types. We hence propose NSD3L as a central epigenetic orchestrator of rRNA transcription in cancer and an enticing therapeutic target for the large group of cancers presenting with NSD3 amplifications and overexpression.