TRANSCRIPTIONAL INDUCTION BY THE HUMAN HMG 14 PROTEIN

细胞的生长、分化和发育是由固定的 基因表达模式。了解这些正常细胞是如何 和生物体过程的进展，以及它们在 不同的疾病状态，需要了解 哺乳动物细胞中的转录。所有的细胞基因都受到调控 在染色质的上下文中，并且长期以来一直被理解为 染色质在决定细胞的激活状态中起着核心作用 一种基因。 已知浓缩染色质既能抑制起始，又能抑制 通过RNA聚合酶延长转录。基因诱导 因此，表达通常需要将染色质重塑为 更具可扩展性的配置，以便既可以访问 特异性DNA结合蛋白及其与一般转录的关系 机械设备。起始点和伸长点必须在 为了有效表达基因，染色质处于活跃状态。 最近，特定的蛋白质或蛋白质的复合体已经被 已鉴定出具有改变染色质结构的能力。在……里面 特别是，我们和其他人已经证明了高度保守的 HMG-14/-17家族蛋白均可改变高阶染色质 通过RNA聚合酶II和III构建和促进转录。 拟议的研究将调查生物化学和生物 HMG-14激活转录的机制。首先，我们将 确定染色质结构中的哪些变化会导致 HMG-14的转录诱导，通过确定是否 HMG-14转录激活区改变组蛋白H1染色质 相互作用或转录活性HMG-14的结合 改变核小体的构象或增强其流动性。 第二，HMG-14靶向特定基因的机制 将通过确定HMG-14的活性是否为 受核心组蛋白乙酰化的影响，以及特异性相互作用是否 HMG-14与DNA结合转录因子的结合可能促进 特定基因的激活。总而言之，这些研究应该定义 并描述了一种新的调节转录的机制 通过在特定基因上重新配置染色质的结构来诱导。

Cell growth, differentiation, and development are driven by fixed patterns of gene expression. Understanding how these normal cellular and organismal processes progress, as well as their disruption in various disease states, requires knowledge of the regulation of transcription in mammalian cells. All cellular genes are regulated within a chromatin context, and it has long been appreciated that chromatin plays a central role in determining the activation state of a gene. Condensed chromatin is known to inhibit both the initiation and elongation of transcription by RNA polymerases. Induction of gene expression therefore often requires remodelling of the chromatin to a more extended configuration, so that it becomes accessible both to specific DNA-binding proteins and to the general transcription machinery. Both initiation and elongation must be facilitated in the active chromatin state in order to efficiently express a gene. Recently, specific proteins or complexes of proteins have been identified that have the capability to alter chromatin structure. In particular, we and others have shown that the highly conserved HMG-14/-17 family of proteins can both alter higher order chromatin structure and facilitate transcription by RNA polymerases II and III. The proposed studies will investigate the biochemical and biological mechanisms whereby HMG-14 activates transcription. First, we will identify which alterations in chromatin structure result in transcriptional induction by HMG-14, by determining whether the transcriptional activation region of HMG-14 alters histone H1-chromatin interactions or whether the binding of transcriptionally active HMG-14 changes the conformation or enhances the mobility of nucleosomes. Second, the mechanism by which HMG-14 may target specific genes for activation will be explored by determining whether HMG-14 activities are influenced by core histone acetylation, and whether specific interaction of HMG-14 with DNA-binding transcription factors may facilitate activation of particular genes. Together, these studies should define and characterize a novel mechanism for mediating transcriptional induction by reconfiguring the structure of chromatin at specific genes.