Ali Syed A, Zaidi Sayyed K, Dacwag Caroline S, Salma Nunciada, Young Daniel W, Shakoori Abdul R, Montecino Martin A, Lian Jane B, van Wijnen Andre J, Imbalzano Anthony N, Stein Gary S, Stein Janet L
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Proc Natl Acad Sci U S A. 2008 May 6;105(18):6632-7. doi: 10.1073/pnas.0800970105. Epub 2008 Apr 29.
Ribosomal RNA (rRNA) genes are down-regulated during osteogenesis, myogenesis, and adipogenesis, necessitating a mechanistic understanding of interrelationships between growth control and phenotype commitment. Here, we show that cell fate-determining factors [MyoD, myogenin (Mgn), Runx2, C/EBPbeta] occupy rDNA loci and suppress rRNA expression during lineage progression, concomitant with decreased rRNA expression and reciprocal loss of occupancy by c-Myc, a proliferation-specific activator of rRNA transcription. We find interaction of phenotypic factors with the polymerase I activator upstream binding factor UBF-1 at interphase nucleoli, and this interaction is epigenetically retained on mitotic chromosomes at nucleolar organizing regions. Ectopic expression and RNA interference establish that MyoD, Mgn, Runx2, and C/EBPbeta each functionally suppress rRNA genes and global protein synthesis. We conclude that epigenetic control of ribosomal biogenesis by lineage-specific differentiation factors is a general developmental mechanism for coordinate control of cell growth and phenotype.
核糖体RNA（rRNA）基因在骨生成、肌生成和脂肪生成过程中表达下调，因此需要从机制上理解生长控制与表型决定之间的相互关系。在此，我们表明细胞命运决定因子[肌分化因子（MyoD）、肌细胞生成素（Mgn）、Runx2、C/EBPβ]在谱系进展过程中占据rDNA位点并抑制rRNA表达，同时rRNA表达降低，而rRNA转录的增殖特异性激活因子c-Myc的占据情况则相反。我们发现表型因子与间期核仁处的聚合酶I激活因子上游结合因子UBF-1相互作用，并且这种相互作用在有丝分裂染色体的核仁组织区被表观遗传保留。异位表达和RNA干扰表明，MyoD、Mgn、Runx2和C/EBPβ各自在功能上抑制rRNA基因和整体蛋白质合成。我们得出结论，谱系特异性分化因子对核糖体生物合成的表观遗传控制是协调细胞生长和表型的一般发育机制。
