Characterization of NSD1 and NSD2 in malignant rhabdoid tumor

Malignant Rhabdoid Tumor (MRT) is an aggressive pediatric tumor driven by a biallelic loss of SMARCB1, a member of the ATP-dependent nucleosome remodeling Brahma-associated factor (BAF) complex. While MRT remains incurable, recent studies suggest that Enhancer of zeste homolog 2 (EZH2) inhibition may offer clinical benefits. However, treatment resistance often develops through the loss of function of a related histone methyltransferase Nuclear Receptor Binding SET Domain Protein 1 (NSD1). NSD1 and a closely related family member NSD2 are responsible for the deposition and maintenance of H3K36me2, a histone modification that acts in opposition to H3K27me3. The disruption of this H3K36me2/H3K27me3 balance due to NSD1 loss is thought to underlie resistance to EZH2 inhibitors, although the reasons for selective NSD1 loss and its precise role in the SMARCB1-deficient context remain poorly understood. To investigate these mechanisms, I used CRISPR-Cas9 to knock out NSD1 and NSD2, individually and in combination, in two MRT cell lines engineered to re-express SMARCB1. Through integrated ChIP-seq and RNA-seq analysis, this study elucidates the roles of NSD1 and NSD2 in shaping the H3K36me2/H3K27me3 landscape and regulating transcription, providing new insights into their function in MRT resistance mechanisms.