Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2

Daniel W. Young, Mohammad Q. Hassan, Jitesh Pratap, Mario Galindo, Sayyed K. Zaidi, Suk-hee Lee, Xiaoqing Yang, Ronglin Xie, Amjad Javed, Jean M. Underwood, Paul Furcinitti, Anthony N. Imbalzano, Sheldon Penman, Jeffrey A. Nickerson, Martin A. Montecino, Jane B. Lian, Janet L. Stein, Andre J. van Wijnen and Gary S. Stein ()
Additional contact information
Daniel W. Young: University of Massachusetts Medical School
Mohammad Q. Hassan: University of Massachusetts Medical School
Jitesh Pratap: University of Massachusetts Medical School
Mario Galindo: University of Massachusetts Medical School
Sayyed K. Zaidi: University of Massachusetts Medical School
Suk-hee Lee: University of Massachusetts Medical School
Xiaoqing Yang: University of Massachusetts Medical School
Ronglin Xie: University of Massachusetts Medical School
Amjad Javed: University of Massachusetts Medical School
Jean M. Underwood: University of Massachusetts Medical School
Paul Furcinitti: University of Massachusetts Medical School
Anthony N. Imbalzano: University of Massachusetts Medical School
Sheldon Penman: Massachusetts Institute of Technology
Jeffrey A. Nickerson: University of Massachusetts Medical School
Martin A. Montecino: Universidad de Concepcion
Jane B. Lian: University of Massachusetts Medical School
Janet L. Stein: University of Massachusetts Medical School
Andre J. van Wijnen: University of Massachusetts Medical School
Gary S. Stein: University of Massachusetts Medical School

Nature, 2007, vol. 445, issue 7126, 442-446

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05473

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