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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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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