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The histone methyltransferase NSD3 enhances rDNA transcription in cancer

ABSTRACT: The histone methyltransferase NSD3 is one of the most recurrently amplified oncogenes in several cancer types and yet how NSD3 promotes tumorigenesis remains largely unknown. Most studies have focused on the short isoform of NSD3, lacking enzymatic activity while very little is known on the long NSD3 isoform, NSD3L, which also includes the SET methyltransferase domain. We found that NSD3L is a key regulator of ribosome biogenesis in cancer. NSD3L localises in the nucleolus and interacts with several nucleolar proteins. NSD3L overexpression is associated with enhanced expression of nucleolar genes and ribosomal RNA (rRNA) transcription in several tumour types. In cancer cells, but not in immortalised fibroblasts, NSD3L knock-down abrogates rRNA transcription and the binding to the entire sequence of ribosomal DNA of Polymerase I, as well as of the PolI activator upstream binding factor UBF, both required for rRNA transcription. Cut&Tag analyses demonstrated that NSD3 localises genome-wide on promoters. Conversely, on rDNA, NSD3L binds upstream of the rRNA transcription start site to a narrow sequence bound also by the FOS/JUN transcription factors. NSD3L deposits di- and tri- methyl groups to the histone lysine 36 on histone H3 throughout the entire rDNA sequences, competing with the histone methyltransferase SUV4-H20, thus preventing the deposition of the repressive histone mark H4K20me3. We propose NSD3L as one of the first chromatin remodelers actively promoting rRNA transcription and ribosome biogenesis. These findings usher novel therapeutic opportunities to target cancers presenting with NSD3 overexpression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224372 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Transcription of the several hundred of mouse and human Ribosomal RNA (rRNA) genes accounts for the majority of RNA synthesis in the cell nucleus and is the determinant of cytoplasmic ribosome abundance, a key factor in regulating gene expression. The rRNA genes, referred to globally as the rDNA, are clustered as direct repeats at the Nucleolar Organiser Regions, NORs, of several chromosomes, and in many cells the active repeats are transcribed at near saturation levels. The rDNA is also a hotspot of recombination and chromosome breakage, and hence understanding its control has broad importance. Despite the need for a high level of rDNA transcription, typically only a fraction of the rDNA is transcriptionally active, and some NORs are permanently silenced by CpG methylation. Various chromatin-remodelling complexes have been implicated in counteracting silencing to maintain rDNA activity. However, the chromatin structure of the active rDNA fraction is still far from clear. Here we have combined a high-resolution ChIP-Seq protocol with conditional inactivation of key basal factors to better understand what determines active rDNA chromatin. The data resolve questions concerning the interdependence of the basal transcription factors, show that preinitiation complex formation is driven by the architectural factor UBF (UBTF) independently of transcription, and exclude a significant role for termination by a torpedomechanism. They further reveal the existence of an asymmetric Boundary Complex formed by CTCF, Cohesin and three phased nucleosomes lying adjacent to the rDNA Enhancer and an arrested RNA Polymerase I complex. We find that this complex is the only site of active histone modification in the whole 45kbp rDNA repeat. Strikingly, the Enhancer Boundary Complex not only delimits each functional rRNA gene, but also is stably maintained after gene inactivation and the re-establishment of surrounding repressive chromatin. Our data define the poised state of rDNA chromatin and place the Enhancer Boundary Complex as the likely entry point for the chromatin remodelling complexes.

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The histone methyltransferase NSD3 enhances rDNA transcription in cancer

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