title: c-MYC coordinately regulates ribosomal gene chromatin remodeling and Pol I availability during granulocyte differentiation.
abstract: Loss of c-MYC is required for downregulation of ribosomal RNA (rRNA) gene (rDNA) transcription by RNA Polymerase I (Pol I) during granulocyte differentiation. Here, we demonstrate a robust reduction of Pol I loading onto rDNA that along with a depletion of the MYC target gene upstream binding factor (UBF) and a switch from epigenetically active to silent rDNA accompanies this MYC reduction. We hypothesized that MYC may coordinate these mechanisms via direct regulation of multiple components of the Pol I transcription apparatus. Using gene expression arrays we identified a 'regulon' of Pol I factors that are both downregulated during differentiation and reinduced in differentiated granulocytes upon activation of the MYC-ER transgene. This regulon includes the novel c-MYC target genes RRN3 and POLR1B. Although enforced MYC expression during granulocyte differentiation was sufficient to increase the number of active rRNA genes, its activation in terminally differentiated cells did not alter the active to inactive gene ratio despite increased rDNA transcription. Thus, c-MYC dynamically controls rDNA transcription during granulocytic differentiation through the orchestrated transcriptional regulation of core Pol I factors and epigenetic modulation of number of active rRNA genes.
authors.affiliation: Division of Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia. gretchen.poortinga@petermac.org
authors.forename: Gretchen
authors.initials: G
authors.lastname: Poortinga
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanij
authors.forename: Kasia
authors.initials: K
authors.lastname: Siwicki
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.forename: Daniel
authors.initials: D
authors.lastname: Brown
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Holloway
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D004256:DNA Polymerase I / Q000378:metabolism*; D004275:DNA, Ribosomal / Q000378:metabolism; D020869:Gene Expression Profiling; D020459:Genes, rRNA; D006098:Granulocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D004275:DNA, Ribosomal; D035463:Pol1 Transcription Initiation Complex Proteins; D016271:Proto-Oncogene Proteins c-myc; C063844:transcription factor UBF; D004256:DNA Polymerase I