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.
The Runx2 (CBFA1/AML3/PEBP2␣A) transcription factor promotes skeletal cell differentiation, but it also has a novel cell growth regulatory activity in osteoblasts. We addressed here whether Runx2 activity is functionally linked to cell cycle-related mechanisms that control normal osteoblast proliferation and differentiation. We found that the levels of
During cell division, cessation of transcription is coupled with mitotic chromosome condensation. A fundamental biological question is how gene expression patterns are retained during mitosis to ensure the phenotype of progeny cells. We suggest that cell fate-determining transcription factors provide an epigenetic mechanism for the retention of gene expression patterns during cell division. Runx proteins are lineage-specific transcription factors that are essential for hematopoietic, neuronal, gastrointestinal, and osteogenic cell fates. Here we show that Runx2 protein is stable during cell division and remains associated with chromosomes during mitosis through sequence-specific DNA binding. Using siRNA-mediated silencing, mitotic cell synchronization, and expression profiling, we identify Runx2-regulated genes that are modulated postmitotically. Novel target genes involved in cell growth and differentiation were validated by chromatin immunoprecipitation. Importantly, we find that during mitosis, when transcription is shut down, Runx2 selectively occupies target gene promoters, and Runx2 deficiency alters mitotic histone modifications. We conclude that Runx proteins have an active role in retaining phenotype during cell division to support lineage-specific control of gene expression in progeny cells.L ineage commitment and cell proliferation are critical for normal tissue development. Preservation of phenotype during clonal expansion of committed cells necessitates the faithful segregation of chromosomes and the conveyance of lineage-specific gene regulatory machinery to progeny cells. Mitosis involves nuclear reorganization, global chromosome condensation, and transcription silencing and occurs concomitant with protein degradation and/or displacement of many regulatory factors from chromosomes (1-4). One fundamental question is how cells are programmed to sustain phenotypic gene expression patterns after cell division when transcriptional competency is restored in progeny cells.Cell fate is determined in response to extracellular cues by lineage-specific master regulators that include the Runx family of transcription factors. In mammals, these proteins are required for development of hematopoietic (Runx1), osteogenic (Runx2), and gastrointestinal and neuronal (Runx3) cell lineages (5-11). Runx factors integrate cell signaling pathways (e.g., TGF-/bone morphogenetic protein and Yes/Src) and recruit chromatin-modifying enzymes (e.g., histone deacetylases, histone acetyltransferases, SWI/SNF, SuVar139) to modulate promoter accessibility within a nucleosomal context (10,(12)(13)(14)(15)(16)(17). Runx proteins function as promoter-bound scaffolds that organize the regulatory machinery for gene expression within punctate subnuclear domains during interphase (18,19). Pathological perturbations in the organization of these domains are linked with altered development and tumorigenesis (10,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Temporal and spatial changes of these architecturally organized Runx domains occur during...
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