title: Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia.
abstract: Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression.
authors.affiliation: Institut Curie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Ridinger-Saison
authors.forename: E
authors.initials: E
authors.lastname: Evanno
authors.forename: I
authors.initials: I
authors.lastname: Gallais
authors.forename: P
authors.initials: P
authors.lastname: Rimmelé
authors.forename: D
authors.initials: D
authors.lastname: Selimoglu-Buet
authors.forename: E
authors.initials: E
authors.lastname: Sapharikas
authors.forename: F
authors.initials: F
authors.lastname: Moreau-Gachelin
authors.forename: C
authors.initials: C
authors.lastname: Guillouf
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C423918:Spic protein, mouse; C494163:Suz12 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2