Phase-separated nuclear bodies of nucleoporin fusions, SET-NUP214 and NUP98-HOXA9, promote condensation of MLL1 and CRM1 to activate target genes

Abstract

Nucleoporins NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies. However, the function and physiological significance of these nuclear bodies remain largely unknown. Previously, we reported that both NUP98-HOXA9 and SET-NUP214 are recruited to HOX cluster regions via chromatin-bound CRM1, a nuclear export receptor (Oka et al., 2019). Here, we show that these nuclear bodies promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase which is essential for the maintenance of HOX gene expression. Our analysis revealed that SET-NUP214 and CRM1 robustly associate with MLL1 to form nuclear bodies and are colocalized on chromatin. We also showed that MLL1 and CRM1 are recruited to the nuclear bodies of NUP98-HOXA9 and that the NUP98-HOXA9/CRM1/MLL1 complex accumulates on its target gene loci, including HOX clusters and MEIS1. These phenomena were not observed in phase-separation-deficient mutants or non-DNA-binding mutants of NUP98-HOXA9. Collectively, these results show that both phase separation and proper targeting of nucleoporin fusions to specific sites could enhance the activation of a wide range of target genes by promoting the condensation of MLL1 and CRM1.