SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes

Mol Cell. 2016 Mar 17;61(6):859-73. doi: 10.1016/j.molcel.2016.02.024.

Abstract

Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Cell Line, Tumor
  • Chromatin / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Leukemic
  • Histone-Lysine N-Methyltransferase / biosynthesis*
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Methylation
  • Minor Histocompatibility Antigens
  • Myeloid-Lymphoid Leukemia Protein / biosynthesis*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Protein Binding
  • Protein Isoforms / genetics
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Transcription, Genetic*

Substances

  • Chromatin
  • DNA-Binding Proteins
  • KMT2A protein, human
  • MEN1 protein, human
  • Minor Histocompatibility Antigens
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • SON protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase