title: Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2.
abstract: Regulation of ribosomal RNA genes is a fundamental process that supports the growth of cells and is tightly coupled with cell differentiation. Although rRNA transcriptional control by RNA polymerase I (Pol I) and associated factors is well studied, the lineage-specific mechanisms governing rRNA expression remain elusive. Runt-related transcription factors Runx1, Runx2 and Runx3 establish and maintain cell identity, and convey phenotypic information through successive cell divisions for regulatory events that determine cell cycle progression or exit in progeny cells. Here we establish that mammalian Runx2 not only controls lineage commitment and cell proliferation by regulating genes transcribed by RNA Pol II, but also acts as a repressor of RNA Pol I mediated rRNA synthesis. Within the condensed mitotic chromosomes we find that Runx2 is retained in large discrete foci at nucleolar organizing regions where rRNA genes reside. These Runx2 chromosomal foci are associated with open chromatin, co-localize with the RNA Pol I transcription factor UBF1, and undergo transition into nucleoli at sites of rRNA synthesis during interphase. Ribosomal RNA transcription and protein synthesis are enhanced by Runx2 deficiency that results from gene ablation or RNA interference, whereas induction of Runx2 specifically and directly represses rDNA promoter activity. Runx2 forms complexes containing the RNA Pol I transcription factors UBF1 and SL1, co-occupies the rRNA gene promoter with these factors in vivo, and affects local chromatin histone modifications at rDNA regulatory regions. Thus Runx2 is a critical mechanistic link between cell fate, proliferation and growth control. Our results suggest that lineage-specific control of ribosomal biogenesis may be a fundamental function of transcription factors that govern cell fate.
authors.affiliation: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Young
authors.forename: Mohammad Q
authors.initials: MQ
authors.lastname: Hassan
authors.forename: Jitesh
authors.initials: J
authors.lastname: Pratap
authors.forename: Mario
authors.initials: M
authors.lastname: Galindo
authors.forename: Sayyed K
authors.initials: SK
authors.lastname: Zaidi
authors.forename: Suk-hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yang
authors.forename: Ronglin
authors.initials: R
authors.lastname: Xie
authors.forename: Amjad
authors.initials: A
authors.lastname: Javed
authors.forename: Jean M
authors.initials: JM
authors.lastname: Underwood
authors.forename: Paul
authors.initials: P
authors.lastname: Furcinitti
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Imbalzano
authors.forename: Sheldon
authors.initials: S
authors.lastname: Penman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Nickerson
authors.forename: Martin A
authors.initials: MA
authors.lastname: Montecino
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
mesh_terms: D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage; D002842:Chromatids / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency / Q000378:metabolism*; D004275:DNA, Ribosomal / Q000235:genetics; D020459:Genes, rRNA / Q000235:genetics*; D006801:Humans; D007399:Interphase; D008677:Metaphase; D051379:Mice; D008938:Mitosis / Q000235:genetics; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D012318:RNA Polymerase I / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004275:DNA, Ribosomal; D009097:Multienzyme Complexes; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C493709:RUNX2 protein, human; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; C063844:transcription factor UBF; D012318:RNA Polymerase I