Transcriptional Regulation by Chromatin Modifiers

描述（由申请人提供）：通过染色质结构的变化在时间和空间上调节转录。通过形成转录活性或非活性染色质的基因调控是稳定的，成为负责将基因活性遗传给后代细胞的细胞记忆系统。在静止期细胞中，这些机制似乎涉及对多种基因的稳定长期抑制，这些基因负责细胞增殖。事实上，这种“不必要的”基因的密封对于维持静止状态至关重要。因此，这种沉默机制中的任何缺陷都会导致静止细胞中“不必要的”基因的表达，从而导致肿瘤发生。虽然已经通过遗传筛选鉴定了许多导致沉默的因素，但它们促进非活性染色质形成的机制仍然很不清楚。为了探索这些机制，我们纯化了一种关键蛋白复合物，它在静止细胞中形成非活性染色质中起重要作用。这种复合物的进一步表征将提供新的见解机制，正常细胞保持静止状态，并进一步，转录在肿瘤细胞中受到干扰。 此外，我们将研究转录活性的模式是如何传递给后代细胞的。一些证据表明，组蛋白H2AZ，一个主要的组蛋白变体，占总H2A的5%至10%，沉积在转录活性染色质上。为了揭示组蛋白H2AZ掺入活性染色质并促进基因活化的机制，我们纯化了至少两种含H2AZ的复合物。这些复合物的功能分析将解决，至少部分地，组蛋白H2AZ如何发挥其特定的和不同的影响，以传递转录活性染色质的模式到后代细胞的难题。

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.