title: AF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription.
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.
authors.affiliation: Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okuda
authors.affiliation: 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.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Medical Research Support Center, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ito
authors.affiliation: 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.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012318:RNA Polymerase I / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D035463:Pol1 Transcription Initiation Complex Proteins; C091129:TAF1B protein, human; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II; D012318:RNA Polymerase I