AF4 Uses the SL1 Components of RNAP1 Machinery to Initiate MLL Fusion- And AEP-dependent Transcription

Nat Commun. 2015 Nov 23;6:8869. doi: 10.1038/ncomms9869.

Abstract

Gene rearrangements generate MLL fusion genes, which can lead to aggressive leukemia. In most cases, MLL fuses with a gene encoding a component of the AEP (AF4 family/ENL family/P-TEFb) coactivator complex. MLL-AEP fusion proteins constitutively activate their target genes to immortalize haematopoietic progenitors. Here we show that AEP and MLL-AEP fusion proteins activate transcription through selectivity factor 1 (SL1), a core component of the pre-initiation complex (PIC) of RNA polymerase I (RNAP1). The pSER domain of AF4 family proteins associates with SL1 on chromatin and loads TATA-binding protein (TBP) onto the promoter to initiate RNA polymerase II (RNAP2)-dependent transcription. These results reveal a previously unknown transcription initiation mechanism involving AEP and a role for SL1 as a TBP-loading factor in RNAP2-dependent gene activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Pol1 Transcription Initiation Complex Proteins / genetics
  • Pol1 Transcription Initiation Complex Proteins / metabolism*
  • Promoter Regions, Genetic
  • RNA Polymerase I / genetics
  • RNA Polymerase I / metabolism*
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Transcription, Genetic*
  • Transcriptional Elongation Factors

Substances

  • DNA-Binding Proteins
  • KMT2A protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Pol1 Transcription Initiation Complex Proteins
  • TAF1B protein, human
  • Transcriptional Elongation Factors
  • Myeloid-Lymphoid Leukemia Protein
  • AFF1 protein, human
  • Histone-Lysine N-Methyltransferase
  • RNA Polymerase II
  • RNA Polymerase I