NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis

Nat Cell Biol. 2007 Jul;9(7):804-12. doi: 10.1038/ncb1608. Epub 2007 Jun 24.

Abstract

Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Acute Disease
  • Amino Acid Sequence
  • Animals
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Histone Methyltransferases
  • Histones / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology*
  • Methylation
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation
  • Myeloid Progenitor Cells / physiology
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / physiology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Spectrophotometry, Atomic
  • Transcriptional Activation
  • Translocation, Genetic

Substances

  • Histones
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • NUP98-NSD1 protein, human
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • Nup98 protein, human
  • Oncogene Proteins, Fusion
  • HoxA protein
  • Histone Methyltransferases
  • NSD1 protein, human