title: Psip1/Ledgf p75 restrains Hox gene expression by recruiting both trithorax and polycomb group proteins.
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.
authors: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK Wendy.Bickmore@igmm.ed.ac.uk.
authors: Madapura M
authors: MM
authors: Pradeepa
authors: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors: Graeme R
authors: GR
authors: Grimes
authors: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors: Gillian C A
authors: GC
authors: Taylor
authors: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors: Heidi G
authors: HG
authors: Sutherland
authors: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK Wendy.Bickmore@igmm.ed.ac.uk.
authors: Wendy A
authors: WA
authors: Bickmore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C489421:Bmi1 protein, mouse; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; C504650:Psip1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D063150:Polycomb Repressive Complex 1