NONO enhances mRNA processing of super-enhancer-associated GATA2 and HAND2 genes in neuroblastoma

Song Zhang, Jack A.L. Cooper, Yee Seng Chong, Alina Naveed, Chelsea Mayoh, Nisitha Jayatilleke, Tao Liu, Sebastian Amos, Simon Kobelke, Andrew C. Marshall, Oliver Meers, Yu Suk Choi, Charles S. Bond, Archa H. Fox

Research output: Contribution to journalArticlepeer-review

Abstract

High-risk neuroblastoma patients have poor survival rates and require better therapeutic options. High expression of a multifunctional DNA and RNA-binding protein, NONO, in neuroblastoma is associated with poor patient outcome; however, there is little understanding of the mechanism of NONO-dependent oncogenic gene regulatory activity in neuroblastoma. Here, we used cell imaging, biochemical and genome-wide molecular analysis to reveal complex NONO-dependent regulation of gene expression. NONO forms RNA- and DNA-tethered condensates throughout the nucleus and undergoes phase separation in vitro, modulated by nucleic acid binding. CLIP analyses show that NONO mainly binds to the 5′ end of pre-mRNAs and modulates pre-mRNA processing, dependent on its RNA-binding activity. NONO regulates super-enhancer-associated genes, including HAND2 and GATA2. Abrogating NONO RNA binding, or phase separation activity, results in decreased expression of HAND2 and GATA2. Thus, future development of agents that target RNA-binding activity of NONO may have therapeutic potential in this cancer context.
Original languageEnglish
Article numbere54977
Number of pages19
JournalEMBO Reports
DOIs
Publication statusE-pub ahead of print - 23 Nov 2022

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