Transcriptional Regulation by Chromatin Modifiers

描述（由申请人提供）：转录通过染色质结构的变化在时间和空间上受到调节。通过转录活性或非活性染色质形成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。在静止细胞中，这些机制似乎参与了对多种负责细胞增殖的基因的长期稳定抑制。事实上，这种封闭“不必要的”基因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，从而导致肿瘤发生。虽然通过基因筛选已经确定了许多导致沉默的因素，但它们促成非活性染色质形成的机制仍然很大程度上不清楚。为了探索这些机制，我们纯化了一个在静止细胞中非活性染色质形成中起重要作用的关键蛋白复合物。该复合物的进一步表征将为正常细胞维持静止状态的机制以及肿瘤细胞中转录受到干扰的机制提供新的见解。

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.