title: CBFβ and the leukemogenic fusion protein CBFβ-SMMHC associate with mitotic chromosomes to epigenetically regulate ribosomal genes.
abstract: Mitotic bookmarking is an epigenetic control mechanism that sustains gene expression in progeny cells; it is often found in genes related to the maintenance of cellular phenotype and growth control. RUNX transcription factors regulate a broad spectrum of RNA Polymerase (Pol II) transcribed genes important for lineage commitment but also regulate RNA Polymerase I (Pol I) driven ribosomal gene expression, thus coordinating control of cellular identity and proliferation. In this study, using fluorescence microscopy and biochemical approaches we show that the principal RUNX co-factor, CBFβ, associates with nucleolar organizing regions (NORs) during mitosis to negatively regulate RUNX-dependent ribosomal gene expression. Of clinical relevance, we establish for the first time that the leukemogenic fusion protein CBFβ-SMMHC (smooth muscle myosin heavy chain) also associates with ribosomal genes in interphase chromatin and mitotic chromosomes to promote and epigenetically sustain regulation of ribosomal genes through RUNX factor interactions. Our results demonstrate that CBFβ contributes to the transcriptional regulation of ribosomal gene expression and provide further understanding of the epigenetic role of CBFβ-SMMHC in proliferation and maintenance of the leukemic phenotype.
authors: Department of Biochemistry and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors: Cesar
authors: C
authors: Lopez-Camacho
authors: Andre J
authors: AJ
authors: van Wijnen
authors: Jane B
authors: JB
authors: Lian
authors: Janet L
authors: JL
authors: Stein
authors: Gary S
authors: GS
authors: Stein
mesh_terms: D045744:Cell Line, Tumor; D002875:Chromosomes / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D050658:Core Binding Factor beta Subunit / Q000502:physiology*; D004256:DNA Polymerase I / Q000378:metabolism; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia; D008938:Mitosis; D018995:Myosin Heavy Chains / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D012270:Ribosomes / Q000235:genetics* / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; C509903:MYH11 protein, human; D015514:Oncogene Proteins, Fusion; C493709:RUNX2 protein, human; D004256:DNA Polymerase I; D018995:Myosin Heavy Chains
keywords: CORE BINDING FACTOR β; EPIGENETICS; LEUKEMIA; MITOTIC BOOKMARKING; RIBOSOMAL GENE EXPRESSION; RIBOSOMAL RNA (rRNA); TRANSCRIPTION COACTIVATORS