Transcriptional Regulation by Chromatin Modifiers

描述(申请人提供)：转录通过染色质结构的变化在时间和空间上进行调节。通过形成转录活性或非活性染色质的基因调控是一种稳定的细胞记忆系统，负责将基因活性遗传给后代细胞。在静止的细胞中，这些机制似乎涉及对多种基因的长期稳定抑制，这些基因负责细胞增殖。事实上，这种对“不必要的”基因的封存对于维持静止状态至关重要。因此，这种沉默机制的任何缺陷都会导致静止细胞中“不必要”基因的表达，从而导致肿瘤的发生。虽然许多导致沉默的因素已经通过基因筛选被确定，但它们促进非活性染色质形成的机制仍很不清楚。为了探索这些机制，我们纯化了一个关键的蛋白质复合体，它在静止细胞中非活性染色质的形成中起着重要作用。对该复合体的进一步表征将为正常细胞维持静止状态以及进一步干扰肿瘤细胞转录的机制提供新的见解。 此外，我们将研究转录活动模式是如何传递给后代细胞的。一些证据表明，组蛋白H_2AZ是一种主要的组蛋白变体，占总H_2A的5%到10%，沉积在转录活性的染色质上。为了揭示组蛋白H_2AZ与活性染色质结合并促进基因激活的机制，我们纯化了至少两个含有H_2AZ的复合体。对这些复合体的功能分析将至少部分解开组蛋白H2 AZ如何发挥其特定和不同的作用，将转录活性染色质模式传递给后代细胞的谜题。

DESCRIPTION (provided by applicant): Transcription is temporally and spatially regulated via changes in chromatin structure. Gene regulation via formation of transcriptionally active or inactive chromatin is stable' d to be a cellular memory system that is responsible for the inheritance of gene activity to progeny cells. In quiescent cells, these mechanisms appear to be involved in stable long-term repression of a variety of genes, which are responsible for cell proliferation. Indeed, such sealing of "unnecessary" genes is crucial for maintaining the quiescent state. Accordingly, any defect in such silencing mechanisms results in the expression of "unnecessary" genes in quiescent cells, leading to tumorigenesis. While many factors that are responsible for silencing have been identified by genetic screening, mechanisms by which they contribute to the formation of inactive chromatin remain largely unclear. To explore these mechanisms, we have purified a key protein complex that plays important roles in the formation of inactive chromatin in quiescent cells. Further characterization of this complex will provide new insights into mechanisms by which normal cells maintain the quiescent state, and further, by which transcription is perturbed in tumor cells. Moreover, we will investigate how the patterns of transcriptional activity are transmitted to progeny cells. Several lines of evidence suggest that histone H2AZ, a major histone variant that occupies 5% to 10% of total H2A, is deposited onto transcriptionally active chromatin. To reveal mechanisms by which histone H2AZ is incorporated into active chromatin and contribute to gene activation, we have purified at least two H2AZ-containing complexes. Functional analyses of these complexes will solve, at least in part, the puzzle of how histone H2AZ exerts its specific and diverse effects to transmit the patterns of transcriptionally active chromatin to progeny cells.