Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure

Cell Rep. 2023 Aug 29;42(8):112884. doi: 10.1016/j.celrep.2023.112884. Epub 2023 Jul 29.

Abstract

NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression. These nuclear bodies are robustly associated with MLL1/CRM1 and co-localized on chromatin. Furthermore, whole-genome chromatin-conformation capture analysis reveals that NUP98::HOXA9 induces a drastic alteration in high-order genome structure at target regions concomitant with the generation of chromatin loops and/or rearrangement of topologically associating domains in a phase-separation-dependent manner. Collectively, these results show that the phase-separated nuclear bodies of nucleoporin fusion proteins can enhance the activation of target genes by promoting the condensation of MLL1/CRM1 and rearrangement of the 3D genome structure.

Keywords: 3D genome; CP: Molecular biology; CRM1; HOX cluster genes; MLL1; NUP214; NUP98; fusion gene; leukemia; molecular condensation; phase separation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin
  • Homeodomain Proteins / metabolism
  • Humans
  • Karyopherins / genetics
  • Karyopherins / metabolism
  • Leukemia* / metabolism
  • Nuclear Bodies
  • Nuclear Pore Complex Proteins* / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism

Substances

  • Nuclear Pore Complex Proteins
  • Karyopherins
  • Homeodomain Proteins
  • Chromatin
  • Receptors, Cytoplasmic and Nuclear