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 elusive1. Runt-related transcription factors Runx1, Runx2 and Runx3 establish and maintain cell identity2, and convey phenotypic information through successive cell divisions for regulatory events that determine cell cycle progression or exit in progeny cells3. 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.
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References
Russell, J. & Zomerdijk, J. C. RNA-polymerase-I-directed rDNA transcription, life and works. Trends Biochem. Sci. 30, 87–96 (2005)
Blyth, K., Cameron, E. R. & Neil, J. C. The runx genes: gain or loss of function in cancer. Nature Rev. Cancer 5, 376–387 (2005)
Zaidi, S. K. et al. Mitotic partitioning and selective reorganization of tissue specific transcription factors in progeny cells. Proc. Natl Acad. Sci. USA 100, 14852–14857 (2003)
Zaidi, S. K. et al. A specific targeting signal directs Runx2/Cbfa1 to subnuclear domains and contributes to transactivation of the osteocalcin gene. J. Cell Sci. 114, 3093–3102 (2001)
Javed, A. et al. Groucho/TLE/R-Esp proteins associate with the nuclear matrix and repress RUNX (CBFα/AML/PEBP2α) dependent activation of tissue-specific gene transcription. J. Cell Sci. 113, 2221–2231 (2000)
Martinez-Balbas, M. A. et al. Displacement of sequence-specific transcription factors from mitotic chromatin. Cell 83, 29–38 (1995)
Muchardt, C. et al. The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are phosphorylated and excluded from the condensed chromosomes during mitosis. EMBO J. 15, 3394–3402 (1996)
Nuthall, H. N., Joachim, K., Palaparti, A. & Stifani, S. A role for cell cycle-regulated phosphorylation in Groucho-mediated transcriptional repression. J. Biol. Chem. 277, 51049–51057 (2002)
Prasanth, K. V., Sacco-Bubulya, P. A., Prasanth, S. G. & Spector, D. L. Sequential entry of components of gene expression machinery into daughter nuclei. Mol. Biol. Cell 14, 1043–1057 (2003)
Gonzalez, I. L. & Sylvester, J. E. Human rDNA: evolutionary patterns within the genes and tandem arrays derived from multiple chromosomes. Genomics 73, 255–263 (2001)
Galindo, M. et al. The bone-specific expression of RUNX2 oscillates during the cell cycle to support a G1 related anti-proliferative function in osteoblasts. J. Biol. Chem. 280, 20274–20285 (2005)
Javed, A. et al. Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo.. Proc. Natl Acad. Sci. USA 102, 1454–1459 (2005)
Mais, C. et al. UBF-binding site arrays form pseudo-NORs and sequester the RNA polymerase I transcription machinery. Genes Dev. 19, 50–64 (2005)
Gebrane-Younes, J., Fomproix, N. & Hernandez-Verdun, D. When rDNA transcription is arrested during mitosis, UBF is still associated with non-condensed rDNA. J. Cell Sci. 110, 2429–2440 (1997)
Roussel, P. et al. Localization of the RNA polymerase I transcription factor hUBF during the cell cycle. J. Cell Sci. 104, 327–337 (1993)
Cheutin, T. et al. Three-dimensional organization of active rRNA genes within the nucleolus. J. Cell Sci. 115, 3297–3307 (2002)
Budde, A. & Grummt, I. p53 represses ribosomal gene transcription. Oncogene 18, 1119–1124 (1999)
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001)
Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nature Rev. Mol. Cell Biol. 6, 838–849 (2005)
Hannan, K. M. et al. Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1. Oncogene 19, 4988–4999 (2000)
Hannan, K. M. et al. RNA polymerase I transcription in confluent cells: Rb downregulates rDNA transcription during confluence-induced cell cycle arrest. Oncogene 19, 3487–3497 (2000)
Voit, R., Schafer, K. & Grummt, I. Mechanism of repression of RNA polymerase I transcription by the retinoblastoma protein. Mol. Cell. Biol. 17, 4230–4237 (1997)
Cavanaugh, A. H. et al. Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product. Nature 374, 177–180 (1995)
Grandori, C. et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nature Cell Biol. 7, 311–318 (2005)
Arabi, A. et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nature Cell Biol. 7, 303–310 (2005)
Poortinga, G. et al. MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation. EMBO J. 23, 3325–3335 (2004)
Valdez, B. C. et al. The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proc. Natl Acad. Sci. USA 101, 10709–10714 (2004)
Otto, F., Kanegane, H. & Mundlos, S. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Hum. Mutat. 19, 209–216 (2002)
Nickerson, J. A., He, D. C., Krochmalnic, G. & Penman, S. Immunolocalization in three dimensions: immunogold staining of cytoskeletal and nuclear matrix proteins in resinless electron microscopy sections. Proc. Natl Acad. Sci. USA 87, 2259–2263 (1990)
Hovhannisyan, H. et al. Maintenance of open chromatin and selective genomic occupancy at the cell-cycle-regulated histone H4 promoter during differentiation of HL-60 promyelocytic leukemia cells. Mol. Cell. Biol. 23, 1460–1469 (2003)
Acknowledgements
We thank I. Grummt for rDNA reagents and J. Rask for editorial assistance. We also thank A. Pardee for discussions. Studies reported were in part supported by the National Institutes of Health.
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Supplementary Information
The file contains Supplementary Figures S1 to S8 with the corresponding legends. These Figures are comprehensive data sets that were included with the original submission before size-reductions in the number and size of the figures; Supplementary Table 1 which contains primer sequences used to generate a subset of our data. The file also contains a list of Runx2 consensus sequences that supports the positioning of red diamonds (i.e., Runx2 sites) on the diagram of the human and mouse rDNA repeats presented in Supplementary Figure S6 and Supplementary Primary Data. This Supplementary Data are digital scans of the original autoradiograms that were used to generate Figure 4. (PDF 8692 kb)
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The file contains Supplementary Methods and additional references. (PDF 168 kb)
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Young, D., Hassan, M., Pratap, J. et al. Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2. Nature 445, 442–446 (2007). https://doi.org/10.1038/nature05473
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DOI: https://doi.org/10.1038/nature05473
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