Paraspeckle protein NONO regulates active chromatin by allosterically stimulating NSD1.

ABSTRACT: Nuclear receptor binding set domain protein 1 (NSD1) is a key histone methyltransferase that catalyzes di-methylation of lysine 36 of histone H3 (H3K36me2), essential for active chromatin domains. While the loss of NSD1 activity halts embryonic development and its aberrant gain drives oncogenesis in leukemia and glioma, the regulatory mechanisms remain poorly understood. Here, we uncover that NSD1 requires allosteric activation through the aromatic pocket of its Pro-Trp-Trp-Pro 2 (PWWP2) domain. Surprisingly, NSD1-PWWP2 binds to the non-canonical target, nuclear paraspeckle protein non-POU-domain-containing octamer binding protein (NONO), and this protein-protein interaction allosterically stimulates NSD1. Mouse embryonic stem cells engineered with mutations in the aromatic pocket of NSD1-

SUBMITTER: Hsu CI 

PROVIDER: S-EPMC12539602 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature