Transcription strategies in terminally differentiated cells: shaken to the core
Transcription strategies in terminally differentiated cells: shaken to the core
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DOI：
10.1101/gad.1598007
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发表时间：
2007-09-01
影响因子：
10.5
通讯作者：
Jones, Katherine A.
中科院分区：
文献类型：
--
作者：
Jones, Katherine A.
在真核生物中，成熟组织和细胞类型的形成需要细胞经历一系列调控的步骤，导致最终细胞分化，其中包括永久退出细胞周期和最终停止所有细胞增殖。伴随这一过程的是许多参与正常细胞生长和细胞周期控制的基因的稳定抑制，伴随着核染色质结构的深刻变化，这些变化是由于先前活跃的基因逐渐沉默，并在表观遗传上被修饰形成并性异染色质（Grigoryev et al. 2006）。同时，新激活的信号通路必须诱导各种组织特异性增强子结合蛋白的重新表达、功能或核定位，这些增强子结合蛋白需要调节负责产生和维持分化细胞表型的基因。用于确定细胞命运规范基本原则的一个强大系统是骨骼肌分化或肌发生过程，在此过程中，多电位中胚层前体细胞参与并分化为肌肉细胞命运（Sartorelli and Caretti 2005）。这一过程可以在确定的顺序阶段进行研究，其中前体细胞首先形成未分化的成肌细胞，然后分化融合形成多核肌管，随后成熟为功能性肌纤维。在这一过程中，上游的关键激活因子包括基本螺旋-环-螺旋（bHLH）调节因子MyoD家族成员（MyoD、myogenin、MRF4和Myf5）以及MADS-box因子MEF2家族成员（MEF2- a、MEF2- b、MEF2- c、MEF2- d）。在这个系统中，肌源性bHLH因子与E-box因子（E12, E47）形成异源二聚体，并与MEF2蛋白协同作用，激活骨骼肌特异性基因，同时也形成强大的自我调节反馈回路，确保其自身的持续表达（basel - duby and Olson 2006; Baugh and Hunter 2006）。MEF2也可以独立于MyoD作用，通过其分别与心肌和骨骼肌细胞中的心肌素和MASTR/SAP结构域蛋白结合（Creemers etal . 2006）。此外，MEF2C还直接与Notch共激活因子Mastermind （MamL1）相互作用，其靶向缺失会导致小鼠严重的肌肉萎缩症（Shen et al. 2006）。这些因子聚集了大型肌肉特异性增强子复合物，并与其他dna结合的激活因子（如血清反应因子（SRF））合作，取代抑制因子并招募上调转录所需的共激活因子（Pipes等，2006）。在这一期的《基因与发育》中，Deato和Tjian（2007）描述了分化细胞中以核心转录机制为中心的转录调控的一种显著的新模式。对这些细胞核心启动因子表达的详细分析表明，肌管分化伴随着tata结合蛋白（TBP）以及许多RNA聚合酶II (RNAPII) tata相关因子（TAF）亚基（TAF1, TAF4, TAF9, TAF10）的显著缺失，提示TFIID复合体的大规模灭绝。在RNA和蛋白质水平上检测到的TFIID成分的缺失可能为大规模沉默仅在未分化细胞中需要的基因提供了有效的机制，包括那些控制细胞增殖和细胞周期进展的基因。这些发现证实并扩展了Perletti等人（2001）的早期报告，即在c2c12衍生的肌管和分化的F9中，TBP和TAF4都通过靶向蛋白水解而下调……
The formation of mature tissues and cell types in eukaryotic organisms requires that cells undergo a regulated series of steps leading to terminal cell differentiation, which includes a permanent withdrawal from the cell cycle and the eventual cessation of all cell proliferation. Concomitant with this process is the stable repression of many genes involved in normal cell growth and cell cycle control, accompanied by profound changes in nuclear chromatin structure that arise as previously active genes gradually become silenced and are modified epigenetically to form facultative heterochromatin (Grigoryev et al. 2006). At the same time, newly activated signaling pathways must induce the de novo expression, function, or nuclear localization of the various tissue-specific enhancer-binding proteins needed to regulate the genes responsible for creating and maintaining the differentiated cell phenotype. A powerful system used to identify the fundamental principles of cell fate specification is the process of skeletal muscle differentation, or myogenesis, in which multipotential mesodermal precursor cells commit and differentiate to a muscle cell fate (Sartorelli and Caretti 2005). This process can be studied in defined sequential stages, wherein the precursor cells first commit to form undifferentiated myoblasts, then differentiate and fuse to form multinucleated myotubes, and subsequently mature into functional myofibers. Key upstream activators in this process include members of the MyoD family of basic helix–loop–helix (bHLH) regulators (MyoD, myogenin, MRF4, and Myf5), as well as the MEF2 family of MADS-box factors (MEF2-A, MEF2-B, MEF2-C, MEF2-D). In this system, the myogenic bHLH factors form heterodimers with E-box factors (E12, E47), and function cooperatively with the MEF2 proteins to activate skeletal muscle-specific genes, while also creating strong autoregulatory feedback loops that ensure their own sustained expression (Bassel-Duby and Olson 2006; Baugh and Hunter 2006). MEF2 can also act independently of MyoD through its ability to associate with myocardin and MASTR/SAP domain protein in cardiac and skeletal muscle cells, respectively (Creemers et al. 2006). Moreover, MEF2C also interacts directly with the Notch coactivator, Mastermind (MamL1), the targeted deletion of which causes a severe muscular dystrophy in mice (Shen et al. 2006). These factors assemble large muscle-specific enhancer complexes and cooperate with other DNA-bound activators, such as the serum response factor (SRF), to displace repressors and recruit the coactivators needed to up-regulate transcription (Pipes et al. 2006). In this issue of Genes & Development, Deato and Tjian (2007) describe a remarkable new mode of transcriptional regulation in differentiated cells that is centered on the core transcriptional machinery. Detailed analysis of core promoter factor expression in these cells reveals that myotube differentiation is accompanied by a dramatic loss of the TATA-binding protein (TBP) as well as many of the RNA polymerase II (RNAPII) TATA-associated factor (TAF) subunits (TAF1, TAF4, TAF9, TAF10), suggestive of a wholesale extinction of the TFIID complex. The loss of TFIID components, which was detected at both the RNA and protein level, may provide an effective mechanism for large-scale silencing of genes whose functions are needed only in undifferentiated cells, including those that control cell proliferation and progression through the cell cycle. These findings confirm and extend an earlier report from Perletti et al.(2001) that both TBP and TAF4 are down-regulated by targeted proteolysis in C2C12-derived myotubes and differentiated F9 …