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.

Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential

“…Furthermore, Runx2 up-regulation does not impede cell-cycle progression in cancer cells. In contrast, in normal osteoblasts, Runx2 ablation accelerates proliferation and increases ribosomal gene expression (18,19,29,30). Together these observations indicate that Runx2 may function as a tumor suppressor in some cell types and have oncogenic potential in others.…”

“…Runx2, p53, and pRb all control cell proliferation by regulating cell-cycle progression and mediating cell growth through effects on ribosomal biogenesis (18,19,30,37,38). Abrogation of tumor suppressor pathways controlled by p53 and pRb, which are ubiquitously expressed, results in the development of diverse tumors that are confined to specific tissues (7,8), indicating that lineagespecific mechanisms are involved.…”

“…Genetic studies reveal that Runx1 is essential for definitive hematopoiesis, Runx2 is required for osteogenesis, and Runx3 is involved in gut development as well as neurogenesis (12-16). Runx proteins support epigenetic regulation at mitosis and control ribosomal gene expression during the cell cycle (9)(10)(11)(17)(18)(19). Runx transcription factors are nuclear-scaffolding proteins that integrate signaling pathways by organizing macromolecular complexes in nuclear microenvironments and facilitating chromatin remodeling (20).…”

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

“…(7) The involvement of RUNX2 as a regulator of osteoblast proliferation also was consistent with data obtained in other biologic contexts. (8)(9)(10)(11) More recently, Zaidi and colleagues (12) proposed that RUNX2 functions as a tumor suppressor in primary diploid osteoblasts, whereas Eliseev and colleagues (13) suggested that RUNX2 acts as a proapoptotic factor.…”

Dynamic epigenetic states of ribosomal RNA promoters during the cell cycle

“…Our data is consistent with other reports showing that there is a large increase in pre-rRNA transcript in G 2 with decreases in G 1 . 5,46 Another report done in yeast has found that the levels of rRNA transcript peaks following replication late in S phase. 4 However, this increase during S phase was only two fold, suggesting it may be due to the duplication of the genome, while we observe a 3-4 fold increase.…”