Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins

Nucleic Acids Res. 2014 Aug;42(14):9021-32. doi: 10.1093/nar/gku647. Epub 2014 Jul 23.

Abstract

Trithorax and polycomb group proteins are generally thought to antagonize one another. The trithorax family member MLL (myeloid/lymphoid or mixed-lineage leukemia) is presumed to activate Hox expression, counteracting polycomb-mediated repression. PC4 and SF2 interacting protein 1 (PSIP1)/p75, also known as LEDGF, whose PWWP domain binds to H3K36me3, interacts with MLL and tethers MLL fusion proteins to HOXA9 in leukaemias. Here we show, unexpectedly, that Psip1/p75 regulates homeotic genes by recruiting not only MLL complexes, but also the polycomb group protein Bmi1. In Psip1(-/-) cells binding of Mll1/2, Bmi1 and the co-repressor Ctbp1 at Hox loci are all abrogated and Hoxa and Hoxd mRNA expression increased. Our data not only reveal a potential mechanism of action for Psip1 in the regulation of Hox genes but also suggest an unexpected interplay between proteins usually considered as transcriptional activators and repressors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Signal Transducing / physiology
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation*
  • Genes, Homeobox*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Polycomb Repressive Complex 1 / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Repressor Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Bmi1 protein, mouse
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Proto-Oncogene Proteins
  • Psip1 protein, mouse
  • Repressor Proteins
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • HoxA protein
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Polycomb Repressive Complex 1