Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4165-9. doi: 10.1073/pnas.1000620107. Epub 2010 Feb 16.
Epigenetic control of ribosomal RNA (rRNA) gene transcription by cell type-specific regulators, such as the osteogenic transcription factor Runx2, conveys cellular memory of growth and differentiation to progeny cells during mitosis. Here, we examined whether coregulatory proteins contribute to epigenetic functions that are mitotically transmitted by Runx2 in osteoblastic cells. We show that the transcriptional corepressor Transducin Like Enhancer-1 (TLE1) associates with rRNA genes during mitosis and interphase through interaction with Runx2. Mechanistically, depletion of TLE1 relieves Runx2-mediated repression of rRNA genes transcription and selectively increases histone modifications linked to active transcription. Biologically, loss of TLE-dependent rRNA gene repression coincides with increased global protein synthesis and enhanced cell proliferation. Our findings reinforce the epigenetic marking target genes by phenotypic transcription factors in mitosis and demonstrate a requirement for retention of coregulatory factors to sustain physiological control of gene expression during proliferation of lineage committed cells.
转录因子 Runx2 等细胞类型特异性调控因子对核糖体 RNA(rRNA)基因转录的表观遗传控制，将细胞在有丝分裂过程中的生长和分化记忆传递给子细胞。在这里，我们研究了核心调节蛋白是否有助于通过成骨转录因子 Runx2 在成骨细胞中传递有丝分裂的表观遗传功能。我们发现转录共抑制因子 Transducin Like Enhancer-1（TLE1）通过与 Runx2 的相互作用，在有丝分裂和间期与 rRNA 基因结合。从机制上讲，TLE1 的耗竭解除了 Runx2 对 rRNA 基因转录的抑制作用，并选择性地增加了与活跃转录相关的组蛋白修饰。从生物学上讲，依赖于 TLE 的 rRNA 基因抑制的丧失伴随着整体蛋白质合成的增加和细胞增殖的增强。我们的发现强化了表型转录因子在有丝分裂中对靶基因的表观遗传标记，并证明了在谱系定向细胞增殖过程中保留核心调节因子以维持基因表达的生理控制的必要性。
