AF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription

Hiroshi Okuda; Akinori Kanai; Shinji Ito; Hirotaka Matsui; Akihiko Yokoyama

doi:10.1038/ncomms9869

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.

Authors

Hiroshi Okuda¹, Akinori Kanai², Shinji Ito³, Hirotaka Matsui², Akihiko Yokoyama¹

Affiliations

¹ Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8501, Japan.
² Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
³ Medical Research Support Center, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

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