Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2
Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2
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DOI：
10.1038/nature05473
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发表时间：
2007-01-25
期刊：
影响因子：
64.8
通讯作者：
Stein, Gary S.
中科院分区：
文献类型：
--
作者：
Young, Daniel W.;Hassan, Mohammad Q.;Stein, Gary S.
核糖体RNA基因的调控是支持细胞生长的基本过程，并与细胞分化紧密相关。尽管RNA聚合酶I（Pol I）和相关因子对rRNA转录的控制已得到充分研究，但控制rRNA表达的谱系特异性机制仍然难以捉摸（1）。Runx 1、Runx 2和Runx 3相关转录因子建立并维持细胞身份（2），并通过连续细胞分裂传递表型信息，用于决定细胞周期进展或子代细胞退出的调控事件（3）。在这里，我们建立了哺乳动物Runx2不仅控制谱系承诺和细胞增殖，通过调节基因转录的RNA Pol II，但也作为一个阻遏物RNA Pol I介导的rRNA合成。在浓缩的有丝分裂染色体中，我们发现Runx2保留在rRNA基因所在的核仁组织区的大离散病灶中。这些Runx2染色体灶与开放的染色质相关，与RNA Pol I转录因子UBF 1共定位，并在间期期间在rRNA合成位点处转变为核仁。核糖体RNA转录和蛋白质合成增强Runx2缺陷，导致基因消融或RNA干扰，而Runx2的诱导特异性和直接抑制rDNA启动子活性。Runx2形成含有RNA Pol I转录因子UBF 1和SL 1的复合物，在体内与这些因子共同占据rRNA基因启动子，并影响rDNA调控区的局部染色质组蛋白修饰。因此，Runx2是细胞命运、增殖和生长控制之间的关键机制联系。我们的研究结果表明，核糖体生物发生的谱系特异性控制可能是一个基本的功能，转录因子，管理细胞的命运。
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(1). Runt-related transcription factors Runx1, Runx2 and Runx3 establish and maintain cell identity(2), and convey phenotypic information through successive cell divisions for regulatory events that determine cell cycle progression or exit in progeny cells(3). 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, colocalize 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.